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This feed contains articles for bioRxiv Subject Collection "Cancer Biology"
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<link>https://www.biorxiv.org</link>
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<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.14.725085v1?rss=1">
<title>
<![CDATA[
Nerve growth factor receptor identifies a basal subpopulation linked to poor prognosis and reduced immunotherapy responses in bladder cancer 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.14.725085v1?rss=1
</link>
<description><![CDATA[
Immunotherapy based on immune checkpoint inhibitors (ICIs) has transformed cancer treatment, outperforming conventional therapies in several tumor types. In bladder cancer (BLCA), ICIs represent a standard treatment for recurrent/metastatic patients. However, resistance is frequent, underscoring the need for biomarkers to personalize treatment. Here, we identify nerve growth factor receptor (NGFR) as a biomarker associated with a lower response probability to ICIs in BLCA. We show NGFR expression in a subset of basal tumor cells and that its high expression is associated with poor prognosis in BLCA . Functionally, we found that NGFR is associated with stemness and invasive capacity in bladder cancer. Furthermore, our data suggest NGFR may act through tumor microenvironment remodeling and activation of cancer-associated fibroblasts (CAFs). Together, these findings position NGFR as a candidate marker of poor prognosis in BLCA, with a potential association with ICI treatment outcome that warrants further clinical validation.
]]></description>
<dc:creator><![CDATA[ Garcia-Agullo, J., Santos, V., Kalisz, M., Marques, M., Andrada, E., Berca, C., Martinez de Villarreal, J., Perez-Martinez, M., Eckstein, M., Benitez, R., Caleiras, E., Malats, N., Real, F. X., Peinado, H. ]]></dc:creator>
<dc:date>2026-05-18</dc:date>
<dc:identifier>doi:10.64898/2026.05.14.725085</dc:identifier>
<dc:title><![CDATA[Nerve growth factor receptor identifies a basal subpopulation linked to poor prognosis and reduced immunotherapy responses in bladder cancer]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.14.721695v1?rss=1">
<title>
<![CDATA[
Overweight status drives early tumor microenvironment reprogramming in pancreatic ductal adenocarcinoma: a cell-type-resolved Bayesian hierarchical modeling and interactome analysis 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.14.721695v1?rss=1
</link>
<description><![CDATA[
Background: Obesity significantly increases the risk of prognosis and clinical outcomes in pancreatic ductal adenocarcinoma (PDAC). While research on the interactions between obesity and the tumor microenvironment (TME) is mostly confined to a few interactions at a time, leaving a gap in the comprehensive understanding of obesity-driven PDAC. We set out to develop a cell-type-resolved model of obesity-driven PDAC using bulk transcriptomic data to investigate TME changes. Methods: We conducted an integrated transcriptomic analysis of PDAC patients from the CPTAC-3 cohort (n=140) stratified by BMI. A custom immune and stromal functional gene signature database covering 65 cell types was constructed, followed by LLM-assisted review, overlap control, and validation. BayesPrism deconvolution using matched single-cell references was used to derive expression profiles for each cell type. Stabl, a machine-learning algorithm, was used to identify BMI-associated signatures. Bayesian hierarchical modeling, using both continuous and categorical BMI change, was applied to estimate effect sizes and assess the statistical credibility of the signature changes using the 95% Highest Density Interval (HDI) excluding zero. Virtual multiplex immunofluorescence was generated from whole-slide H&E images using gigaTIME to assess the spatial manifestation of BMI-associated TME changes in tissue Results: Bulk pathway analysis showed that ECM homeostasis and primary immunodeficiency pathways deteriorated with increasing BMI. However, Bayesian modeling revealed cell-type-specific, non-linear dynamics. Stromal populations in overweight (OW) individuals were altered, with changes in ECM synthesis and inflammatory signaling that stabilized rather than intensified during obesity. Immune compartments also showed diverse trajectories: CD4+ T cells remained functional in OW but collapsed in obesity; CD8+ T cells progressed linearly from activation to chronic exhaustion. NK cells exhibited non-monotonic behavior, and monocyte and B cell lineages became impaired prior to clinical obesity. Cell-cell interaction analysis showed a shift from a T cell and dendritic cell-centric adaptive interactome in normal weight patients to a neutrophil-dominated inflammatory network in OW. Spatial analysis showed stromal-trapped CD8+ T cells were compressed closer to the tumor boundary with rising BMI. Conclusions: Overweight status represents a critical tipping point in tumor microenvironmental reprogramming, challenging linear models of obesity-associated immune modulation and suggesting that early metabolic interventions may prevent PDAC functional deterioration.
]]></description>
<dc:creator><![CDATA[ Viswanathan, A., Seby, J., Harikumar, K. B. ]]></dc:creator>
<dc:date>2026-05-17</dc:date>
<dc:identifier>doi:10.64898/2026.05.14.721695</dc:identifier>
<dc:title><![CDATA[Overweight status drives early tumor microenvironment reprogramming in pancreatic ductal adenocarcinoma: a cell-type-resolved Bayesian hierarchical modeling and interactome analysis]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-17</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.14.725132v1?rss=1">
<title>
<![CDATA[
Subclonal IDH1/2 Mutations as a Targetable Vulnerability in Vascular Tumors 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.14.725132v1?rss=1
</link>
<description><![CDATA[
Despite extensive sequencing, the genetic etiology of sporadic angiosarcoma remains poorly defined. Maffucci syndrome, characterized by vascular tumors and elevated cancer risk, is driven by mosaic gain-of-function mutations in IDH1/2, though these have not been reported in sporadic angiosarcoma. We identify recurrent, low-variant allele frequency hotspot mutations in IDH1/2 in over half of sporadic angiosarcomas. Mutations were validated by Sanger sequencing and immunohistochemistry. Mutant IDH1 endothelial cells promote tumorigenesis through non-cell-autonomous mechanisms, secreting 2-hydroxyglutarate (2-HG) to increase growth factor and endothelial-to-mesenchymal transition gene expression, activate pAkt/pERK signaling, induce DNA methylation changes, and promote anchorage-independent growth, which are reversed by the mutant IDH1 inhibitor ivosidenib. Patients with mosaic IDH1 mutations show reduced serum 2-HG and marked tumor regression following ivosidenib treatment. The clinical efficacy of ivosidenib in vascular tumors with subclonal IDH1 mutations suggests that low VAF IDH1/2 mutations may be a targetable vulnerability in sporadic angiosarcoma.
]]></description>
<dc:creator><![CDATA[ Yu, D.-M., Lee, E., Starrett, G. J., Zhai, Z., Dowell, E., Walsh, K., Day, A. T., Palsgrove, D., Bishop, J., Marchione, D., Asgari, M., Chung, S. S., High, W., Teng, J., Wissell, J., Wilky, B., Dlass, D., Hosler, G. A., Wang, R. C. ]]></dc:creator>
<dc:date>2026-05-17</dc:date>
<dc:identifier>doi:10.64898/2026.05.14.725132</dc:identifier>
<dc:title><![CDATA[Subclonal IDH1/2 Mutations as a Targetable Vulnerability in Vascular Tumors]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-17</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724422v1?rss=1">
<title>
<![CDATA[
Reprogramming tumour-associated macrophages from immune suppressive to inflammatory state by Checkpoint kinase 1 inhibitor combination treatment 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724422v1?rss=1
</link>
<description><![CDATA[
Background: Tumour-associated macrophages (TAMs) play critical roles within the tumour microenvironment regulating immune evasion and therapeutic response. Previously, we have shown that the combination of Checkpoint kinase 1 inhibitor (CHK1i) with a subclinical dose of hydroxyurea (LDHU) reprograms the tumour immune microenvironment to a pro-inflammatory status. Methods: We investigated a tumour-restricted Fcgr4 (Cd16.2) expressing macrophage population in multiple murine tumour models and the impact of CHK1i+LDHU on this population, using conventional and imaging flow cytometry as well as single-cell sequencing. Results: Transcriptional profiling using CITE-seq and single-cell RNA sequencing reveals that Fcgr4 TAMs closely resemble Fcgr4- TAMs but display modest enrichment of interferon-associated and inflammatory gene programs, consistent with a functionally biased state rather than a distinct lineage. Importantly, we show that a highly tumour selective CHK1i+LDHU therapy shifts TAMs toward a more inflammatory phenotype while preserving dominant immunosuppressive features. Depletion of CSF1R macrophages enhanced CD8 T cell activation without influencing tumour growth but significantly augmented therapeutic efficacy of CHK1i+LDHU. Conclusion: Together, these findings define a novel TAM population and establish how targeted therapy reshapes, but does not fully overcome, TAM-mediated immune regulation.
]]></description>
<dc:creator><![CDATA[ Zeng, Z., Gandini, A., Bhatt, R., Proctor, M., Guo, J., Millard, S., Wu, S. Y., Dolcetti, R., Wells, J. W., Gonzalez Cruz, J., Irvine, K. M., Gabrielli, B. ]]></dc:creator>
<dc:date>2026-05-17</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724422</dc:identifier>
<dc:title><![CDATA[Reprogramming tumour-associated macrophages from immune suppressive to inflammatory state by Checkpoint kinase 1 inhibitor combination treatment]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-17</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724653v1?rss=1">
<title>
<![CDATA[
Targeting therapy-induced senescence across multiple breast cancer subtypes in a metastatic bone-like microenvironment 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724653v1?rss=1
</link>
<description><![CDATA[
Chemotherapeutic treatment of breast cancer with Doxorubicin (DOX) can induce tumor and stromal cell senescence leading to therapy-resistance. Senescence-associated secretory phenotype (SASP) promotes secretion of pro-inflammatory and tumorigenic factors causing systemic inflammation. Combined, this can result in immune suppression, tumor growth and secondary spread of cancer. Targeting and removing senescent and cancerous cells using a combination of chemotherapeutic and senolytic drugs may reduce systemic inflammation, improve therapeutic efficacy, and prevent metastasis. Exposure of triple-negative breast cancer (MDA-MB-231), hormone-responsive (MCF-7) and HER2+ (MDA-MB-453) cells, and primary spine osteoblasts to DOX showed significant induction of p21-positive senescent cells. DOX and senolytics (RG-7112, o-Vanillin) treatment of co-culture spheroids showed a significant additive effect in reducing tumor sphere viability and growth, indicating reduced metastatic potential. This was correlated with reduced SASP in triple-negative and hormone responsive lines and decreased levels of senescent cells in all subtypes and primary stromal cells, while proliferation was decreased, and apoptosis increased across all breast cancer subtypes. Future chemotherapeutic treatment in breast cancer models may be optimized by adding senolytic drugs to more effectively clear senescent tumor and stromal cells, reducing risk for relapse and metastatic potential, while allowing for tissue regeneration in the bone metastatic environment.
]]></description>
<dc:creator><![CDATA[ Hamburger, E. C. B., Ghazizadeh, S., Cardahi, F., Ouellet, J. A., Weber, M. H., Garzia, L., Haglund, L., Rosenzweig, D. ]]></dc:creator>
<dc:date>2026-05-17</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724653</dc:identifier>
<dc:title><![CDATA[Targeting therapy-induced senescence across multiple breast cancer subtypes in a metastatic bone-like microenvironment]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-17</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724882v1?rss=1">
<title>
<![CDATA[
Cellular stemness identifies high-risk ductal carcinoma in situ and offers a therapeutic interception opportunity 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724882v1?rss=1
</link>
<description><![CDATA[
Ductal carcinoma in situ (DCIS) exhibits substantial heterogeneity in its risk of progression to invasive breast cancer, yet the cellular and molecular determinants of high-risk lesions remain incompletely defined. Using spatially resolved single-cell transcriptomic and epigenomic profiling of 43 patient derived DCIS and DCIS/invasive ductal carcinoma (IDC) samples, we delineate cellular programs, spatial organization, and epigenetic regulatory mechanisms associated with invasive potential. We identify an epithelial population with stemness features within luminal hormone-responsive (LumHR) cells that progressively expands from benign tissue to DCIS and IDC, and is strongly associated with invasive progression and recurrence-linked transcriptional programs. Spatial mapping reveals discrete DCIS niches enriched for stem-like LumHR cells, characterized by elevated CEACAM6 expression and enhanced ligand receptor interactions, including CEACAM6-EGFR signaling between epithelial and stromal compartments, including cancer-associated fibroblasts, macrophages (APOC1 positive) and perivascular cells. These niches define a microenvironmental context that supports stemness and invasive potential. Epigenomic analyses implicate FOXA1 as a key regulator of these stem-like transcriptional states. Pharmacologic disruption of FOXA1 regulatory network using LSD1 inhibition suppresses stemness-associated transcriptional programs in vitro and significantly restrains tumor growth in vivo. Collectively, these findings define high risk DCIS as a stemness-driven disease embedded within specialized microenvironments, and identify associated regulatory networks as candidate biomarkers and therapeutic vulnerabilities.
]]></description>
<dc:creator><![CDATA[ Schueddig, E., Kochat, V., Arslan, E., Dallas, Y., Yang, P., Pedron, W., Li, Z., Henry, R., Lin, J., Mattohti, M., Madan, R., Fields, T., Khan, S., Golem, S., Wagner, J. L., Larson, K. E., Balanoff, C., Aripoli, A., Huppe, A., Winblad, O., Peterson, J., Hill, M., Smith, C., Jeffers, E. E., Kilgore, L. J., Navin, N., Zang, C., Wei, P., Fabian, C., Lewis, M. T., Zhu, Q., Thompson, A. M., Godwin, A. K., Koestler, D. C., Rai, K., Behbod, F. ]]></dc:creator>
<dc:date>2026-05-16</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724882</dc:identifier>
<dc:title><![CDATA[Cellular stemness identifies high-risk ductal carcinoma in situ and offers a therapeutic interception opportunity]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-16</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724215v1?rss=1">
<title>
<![CDATA[
ATF4 programs proline-dependent immune evasion in β-Catenin-driven hepatocellular carcinoma 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724215v1?rss=1
</link>
<description><![CDATA[
Abstract Background & Aims Hepatocellular carcinoma (HCC) frequently exhibits resistance to immune checkpoint inhibitors (ICIs), particularly in {beta} -catenin-driven tumors characterized by immune exclusion. While the Unfolded Protein Response (UPR) and the Integrated Stress Responses (ISR) enable tumor adaptation to metabolic stress their role in shaping tumor immunogenicity remains incompletely understood. We investigated whether ATF4, a central effector of the integrated stress response, couples metabolic reprogramming to suppression of anti-tumor immunity in HCC. Methods We combined transcriptomic analyses across three independent human HCC cohorts with mechanistic studies using an immunotherapy-resistant MYC/{beta}-catenin-driven murine HCC model. We integrated CRISPR/Cas9-mediated deletion of Atf4 with RNA-sequencing and targeted metabolomics. The impact of tumor-derived metabolites on macrophage differentiation and polarization was evaluated using primary bone marrow-derived cells. Therapeutic responses were evaluated in orthotopic and subcutaneous models treated with anti-PD-1 and anti-VEGFA. Results ATF4 and XBP1 transcriptional signatures are selectively enriched in human HCC and associate with poor prognosis, vascular invasion, and an immunosuppressive myeloid-enriched tumor microenvironment. Genetic ablation of Atf4 markedly suppressed tumor growth in immunocompetent but not immunodeficient hosts, establishing a requirement for immune-mediated tumor control. Mechanistically, Atf4 loss downregulated Aldh18a1 and disrupted proline biosynthesis, resulting in extracellular proline depletion. This proline-deficient environment abrogated monocyte-to-macrophage differentiation and decreased M2 polarization, thereby reshaping the tumor microenvironment toward enhanced T cell infiltration and activation. Functionally, Atf4-deficient tumors exhibited restored sensitivity to anti-PD-1 monotherapy and showed pronounced responses to combined anti-PD-1/anti-VEGFA treatment in aggressive orthotopic models. Conclusion ATF4 programs a proline-dependent metabolic axis that sustains macrophage-mediated immunosuppression and immune evasion in {beta}-catenin-driven HCC. Disruption of this pathway converts immune-excluded tumors into T cell-inflamed states and restores responsiveness to immunotherapy. By governing proline homeostasis and macrophage-mediated immunosuppression, ATF4 is a key metabolic checkpoint for immune evasion, linking stress adaptation to immune escape and a candidate therapeutic target in HCC.
]]></description>
<dc:creator><![CDATA[ Infante, S., Santa Maria, E., Finnemore, A., Arcelus, S., Barace, S., Martinez-Montes, A., Garcia-Porrero, G., Hosseini-Giv, N., Miraval, E., de Andrea, C. E., Llopiz, D., Reig, M., Finkelstein, Y., Sangro, B., Sarobe, P., Fortes, P., Uriz-Huarte, A., Bayo, J., Argemi, J. ]]></dc:creator>
<dc:date>2026-05-16</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724215</dc:identifier>
<dc:title><![CDATA[ATF4 programs proline-dependent immune evasion in β-Catenin-driven hepatocellular carcinoma]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-16</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724348v1?rss=1">
<title>
<![CDATA[
Neutral Sphingomyelinase-2 Restrains TAZ to Suppress Breast Tumor Growth 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724348v1?rss=1
</link>
<description><![CDATA[
Loss of tumor suppressor gene (TSG) activity is pervasive across cancers and linked to worse clinical outcomes, yet therapeutic efforts aimed at restoring TSGs have remained elusive. One underexplored avenue to address this problem is the targeting of metabolic signaling pathways that actively enforce tumor suppressive programs. Ceramide (Cer), the central hub of the sphingolipid (SL) metabolic network, has long been thought to have tumor suppressive functions, though its mechanistic roles remain incompletely defined. Here, we identify neutral sphingomyelinase-2 (nSMase2) as a critical mediator of Cer-dependent tumor suppression. We show that nSMase2 is frequently suppressed in breast cancer (BC) and its restoration inhibits tumorigenesis. Biologically, this was linked to suppression of anchorage-independent growth (AIG) and to restraint of the HIPPO pathway effector TAZ, but not its paralog YAP. Taken together, these findings define a previously unrecognized metabolic tumor suppressor pathway, clarify ambiguities in both SL and HIPPO signaling networks, and highlight reactivation of nSMase2-Cer signaling as a potential therapeutic strategy in BC.
]]></description>
<dc:creator><![CDATA[ Resnick, A. E., Franzi, V., Ghandour, B. K., Chiappone, S. B., Lalanne, S., Alexander, M. E., Peperno, D. M., Obeid, J., Pritam, I., Miranda, I. D., Coant, N., Airola, M. V., Damaghi, M., Velazquez, F. N., Hannun, Y. A., Clarke, C. J. ]]></dc:creator>
<dc:date>2026-05-15</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724348</dc:identifier>
<dc:title><![CDATA[Neutral Sphingomyelinase-2 Restrains TAZ to Suppress Breast Tumor Growth]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724601v1?rss=1">
<title>
<![CDATA[
LVV SMRTcap reveals extensive proviral variation in lentiviral vector-transduced CAR T cells 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724601v1?rss=1
</link>
<description><![CDATA[
Lentiviral vectors are commonly used to introduce chimeric antigen receptor transgenes into T cells, but routine assays quantify vector copy number or integration sites without sequencing full-length integrated vectors. HIV-1 proviruses often acquire large deletions and cytidine deaminase-driven hypermutation; whether similar variation occurs in therapeutic lentiviral vectors is unclear. We adapted a novel long-read capture approach to enrich long fragments spanning vector DNA and adjacent human sequence, enabling simultaneous integration-site mapping and proviral integrity analysis with single-molecule resolution. In research-grade CAR T cells produced with an experimental, transient-transfection lentiviral vector workflow, 40% of integrated vectors carried recurrent deletions that removed the internal promoter or parts of the chimeric antigen receptor cassette. The dominant promoter deletion was present in the viral stock. In clinical chimeric antigen receptor T cell products, promoter deletions were less frequent, but detectable pre-infusion and post-infusion. Across datasets we observed widespread G-to-A substitutions consistent with restriction factor editing, including changes predicted to introduce premature stop codons within the transgene open reading frame. Our method reveals proviral variants invisible to standard quality-control assays and provides a framework to improve vector production and monitor transgene integrity in clinical products.
]]></description>
<dc:creator><![CDATA[ Kaiser, C., Sadri, G., Elliott, E. M., Mroczkowska, J. J., Ankita, J., Ferguson, M., Bushman, F., Fraietta, J. A., Rouchka, E. C., Smith, M. ]]></dc:creator>
<dc:date>2026-05-15</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724601</dc:identifier>
<dc:title><![CDATA[LVV SMRTcap reveals extensive proviral variation in lentiviral vector-transduced CAR T cells]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724825v1?rss=1">
<title>
<![CDATA[
Hydrogen Peroxide induces resistance to DNA damage in a localization and p53 dependent manner. 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724825v1?rss=1
</link>
<description><![CDATA[
Organisms need to be able to adapt to a changing environment in order to survive. The adaptive response invoked by a low dose of a stressor resulting in resistance to high levels of that stressor is known as hormesis and can even lead to lifespan extension of organisms. The exact mechanisms underlying stress-induced hormesis are unknown, although multiple studies pose mitochondria-derived Reactive Oxygen Species (ROS, e.g. H2O2) as an important contributor. Here we used chemo-genetic H2O2 production as a model to study ROS-dependent adaptive responses in a localization-dependent manner. We found that brief, sublethal H2O2 production at the nucleosomes provides p53-dependent resistance to a subsequent high dose of H2O2, whereas mitochondrial H2O2 production, surprisingly, does not. A multi-omics approach revealed that p53-induced hormesis is accompanied by metabolic rewiring that boosts reductive capacity, and that the increased stress resistance can mostly be attributed to its downstream target p21. Importantly, brief p53 stabilization also mounted protection against chemotherapy-induced DNA damage, suggesting that p53-dependent hormesis could be exploited to selectively protect healthy, p53-wildtype tissue from chemotherapy in the treatment of patients with p53 mutant tumors.
]]></description>
<dc:creator><![CDATA[ Keijer, J. P., Polderman, P. E., Alcaraz-Sobrevals, P., van Es, R. M., Montiel Gonzalez, D., Kok, R. N. U., El Baghdadi, S., Gülersönmez, C., Stigter, E. C. A., Vos, H. R., Burgering, B. M. T., van Boxtel, R., Dansen, T. B. ]]></dc:creator>
<dc:date>2026-05-15</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724825</dc:identifier>
<dc:title><![CDATA[Hydrogen Peroxide induces resistance to DNA damage in a localization and p53 dependent manner.]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724208v1?rss=1">
<title>
<![CDATA[
Comprehensive Analysis Reveals Adaptive DNA Repair and Replication Stress Networks in Genomically Unstable Breast Cancer 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724208v1?rss=1
</link>
<description><![CDATA[
Genomic instability is a defining hallmark of breast cancer, yet the mechanisms by which tumors tolerate persistent DNA damage remain poorly understood. We performed a comprehensive, multi-cohort analysis of breast cancer datasets to define how DNA damage response (DDR) and replication stress tolerance (RST) networks are rewired in genomically unstable tumors. Using fraction of genome altered (FGA) as a chromosomal instability metric, we show that BRCA-mutant tumors exhibit elevated genomic instability coupled with increased expression of homologous recombination, Fanconi anemia, mismatch repair, base excision repair, and alternative end-joining pathways. Strikingly, heightened pathway activity correlates with increased genome alteration, supporting a model of damage tolerance rather than repair restoration. RST programs, including fork remodeling, protection, and single strand DNA gap suppression, further contribute to tumor fitness under replication stress. These adaptive states are enriched in aggressive subtypes, intensified with progression, and associate with pathway-specific mutational burden. Co-occurrence and mutual exclusivity mapping uncovered non-random subtype-relevant genetic interactions states among major drivers and DDR genes, nominating context-specific synthetic lethal opportunities. Our findings identify compensatory genome-maintenance programs as central drivers of tumor resilience and highlight pathway-specific vulnerabilities for targeted therapeutic intervention.
]]></description>
<dc:creator><![CDATA[ Panday, A., Ramadan, F., Zahraeifard, S., Subedi, U., Shah, S., Yadav, N. ]]></dc:creator>
<dc:date>2026-05-15</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724208</dc:identifier>
<dc:title><![CDATA[Comprehensive Analysis Reveals Adaptive DNA Repair and Replication Stress Networks in Genomically Unstable Breast Cancer]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724607v1?rss=1">
<title>
<![CDATA[
Profilin 1 maintains cell cycle fidelity to prevent unscheduled genome doubling and polyploidy in cancer 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724607v1?rss=1
</link>
<description><![CDATA[
Whole-genome doubling (WGD) represents a major route to genome instability and therapeutic resistance in cancer; yet, the mechanisms enabling genome duplication in p53-proficient cells remain poorly understood. Here, we identify Profilin 1 (PFN1) loss as a driver of WGD through impaired mitotic entry. Using FUCCI live-cell imaging and single-cell genomic profiling, we show that PFN1-deficient cells bypass mitosis and undergo endoreplication, generating tetraploid cells. Rather than undergoing stable arrest after mitotic bypass, these genome-doubled cells retain proliferative capacity and proceed through aberrant mitotic divisions, thereby amplifying genomic instability. Proteomic analyses reveal coordinated attenuation of late cell-cycle programs, including downregulation of key mitotic regulators such as CDK1, PLK1 and CKS2, consistent with impaired G2/M transition. Despite accumulating polyploidy, PFN1-knockout cells fail to activate an effective p53 tetraploidy checkpoint and display increased nuclear MDM2, promoting cell-cycle arrest evasion and chemotherapeutic resistance. We supported clinical relevance by an orthotopic osteosarcoma xenograft model, in which PFN1-deficient SaOS2 cells showed enhanced metastatic dissemination, and by pan-cancer TCGA analyses confirming a recurrent association between PFN1 loss and WGD. Together, these findings identify Profilin 1 as a safeguard of cell-cycle fidelity whose loss enables genome doubling, cellular plasticity and therapy tolerance.
]]></description>
<dc:creator><![CDATA[ Scotto di Carlo, F., Russo, S., Gemble, S., Vitale, N., Mace, A.-S., Harmsen, I. J., Borriello, M. A., Foijer, F., Manfredi, M., Basto, R., Gianfrancesco, F. ]]></dc:creator>
<dc:date>2026-05-15</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724607</dc:identifier>
<dc:title><![CDATA[Profilin 1 maintains cell cycle fidelity to prevent unscheduled genome doubling and polyploidy in cancer]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724869v1?rss=1">
<title>
<![CDATA[
Characterization of tumor interactions with the immune system in an autochthonous mouse model of glioblastoma 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724869v1?rss=1
</link>
<description><![CDATA[
Background : Glioblastoma is an aggressive and incurable brain tumor. Clinical trials of immune checkpoint inhibitors showed no clinical benefit in glioblastoma when given after surgery. However, a clinical trial in which PD1 inhibition was given prior to second surgery did show pharmacodynamic evidence for activity. This suggests the possibility that immune checkpoint inhibitors may be more effective in a setting where large tumors are present. Here we have studied immune responses to large tumors in an autochthonous mouse model of glioblastoma. Methods : Glioblastoma was induced by transfection with oncogenic plasmids injected directly into the lateral ventricle of neonatal mice. Immune responses were assessed using a combination of spectral flow cytometry and immunohistochemistry. Results : There was a marked immune response to large tumors, with significant increases in CD4 T cells and dendritic cells. T cell changes occurred primarily at leptomeningeal/perivascular border sites. A large proportion of CD4 T cells expressed PD1 and half of these were regulatory T cells. NK cells were also increased in mice with large tumors, but were predominantly in immature states. The mouse model accurately recapitulates the formation of palisading necroses. These contain apoptotic cells and avidly recruit myeloid cells that are induced to express large amounts of TGF{beta}. Conclusions : Large glioblastoma tumors generate a border site population of PD1 positive T cells that may explain the pharmacodynamic response in neoadjuvant trials, and a palisading necrosis-driven immunosuppressive mechanism that may explain why responses are insufficient to provide a significant clinical benefit.
]]></description>
<dc:creator><![CDATA[ Lorimer, I., Lui, M., Makinson, O. J., Walsh, M. L., Matthews, T. J., Woulfe, J., Ardolino, M. ]]></dc:creator>
<dc:date>2026-05-15</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724869</dc:identifier>
<dc:title><![CDATA[Characterization of tumor interactions with the immune system in an autochthonous mouse model of glioblastoma]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724782v1?rss=1">
<title>
<![CDATA[
CYCLON is a nucleolar protein that regulates pan-cancer cell fitness through ribosome biogenesis 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724782v1?rss=1
</link>
<description><![CDATA[
Tumor progression is driven by cancer cell fitness, defined as the capacity of malignant cells to maintain growth, adapt to stress and withstand therapy Cellular fitness is fundamentally governed by nucleolar processes, which act as central regulators by integrating RNA processing with ribosome biogenesis to support protein synthesis and stress adaptation. The nuclear protein CYCLON, containing a large intrinsically disordered region (IDR) could be implicated in mediating biomolecular condensates and regulatory plasticity, which are key elements of nucleolar biology. CYCLON also emerged as a candidate regulator of cancer cell fitness, as it is frequently overexpressed across tumor types. Inducible silencing and cell biology approaches have shown that CYCLON maintains nucleolar integrity, controls nucleoli size and number, nucleolin and Ki-67 distribution and prevents nucleolar stress. CYCLON contributes to ribosome biogenesis by binding ribosomal RNA (rRNA) and regulating 32S and 21S pre-rRNA processing, ultimately influencing ribosomal subunit production and global protein synthesis. Its depletion impairs proliferation and clonogenic capacity by prolonging both interphase and mitosis, leading to slowed cell cycle progression. The impact of CYCLON on cellular fitness has been consistently observed across cancer models, reinforcing its essential role in the regulation of nucleolar biology.
]]></description>
<dc:creator><![CDATA[ Garcia-Sandoval, A. C., Durand, S., Roberston, N., Hamaidia, S., Mikolajczyk, J., Bourdelais, F., Montaut, E., Lopez, V., Turowski, T., Tollervey, D., Diaz, J.-J., Destaing, O., Emadali, A. ]]></dc:creator>
<dc:date>2026-05-15</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724782</dc:identifier>
<dc:title><![CDATA[CYCLON is a nucleolar protein that regulates pan-cancer cell fitness through ribosome biogenesis]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724787v1?rss=1">
<title>
<![CDATA[
Identification of non-covalent inhibitors for the atypical peroxiredoxin PRDX5 as a therapeutic strategy in malignant pleural mesothelioma 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724787v1?rss=1
</link>
<description><![CDATA[
Malignant pleural mesothelioma (MPM) is an aggressive asbestos-linked cancer with limited therapeutic options and a dismal 5-year survival rate of [~]5%. While aberrant production of reactive oxygen and nitrogen species (ROS/RNS) is a hallmark of MPM, targeted approaches to exploit these redox vulnerabilities remain scarce. Here, using the MOSAIC multimodal cancer patient atlas, we identify Peroxiredoxin 5 (PRDX5) as being significantly upregulated in the epithelioid subtype of MPM. We show that MPM cells exhibit enhanced resistance to nitrosative and oxidative stress compared to healthy mesothelial cells, a phenotype correlated with basal PRDX5 expression. Next, utilising a machine learning guided discovery pipeline, we identified three putative allosteric pockets in PRDX5 and conducted a virtual screen of 3.6 million compounds. High-throughput biochemical validation of 452 candidates yielded 36 non-covalent hits, including sub-micromolar inhibitors. These findings establish PRDX5 as a novel, subtype specific therapeutic target in MPM and provide a chemical framework for the development of next-generation redox-modulating oncology treatments.
]]></description>
<dc:creator><![CDATA[ Monserrat, J., Montanari, F., Laurent, V., Ancey, P.-B., Jean, N., Jeannu, C., Wang, G., You, G., Shen, Q., Mac Kain, A., Bareche, Y., Herpin, L., Jeremiah, N., Codato, R., Romagnoni, A., Cornish, A. J., Rozhavskaya, E., Pattarini, L., Petit, C., Zindy, P.-J., Shukla, J., Gomez, S., MOSAIC Consortium,, Eckstein, M., Youssef, A., Keilholz, U., Morkel, M., Homicsko, K., Saglietti, C., Shi, L., Zhang, J., Pronier, E. ]]></dc:creator>
<dc:date>2026-05-15</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724787</dc:identifier>
<dc:title><![CDATA[Identification of non-covalent inhibitors for the atypical peroxiredoxin PRDX5 as a therapeutic strategy in malignant pleural mesothelioma]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724405v1?rss=1">
<title>
<![CDATA[
Enhanced Radio-sensitization of Glioblastoma Using a Dendrimer-Based Metformin Nano-formulation through Direct Tumor Suppression and Indirect Immune Modulation 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724405v1?rss=1
</link>
<description><![CDATA[
Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary malignant brain tumor in adults, associated with a dismal median survival of 12 to 15 months post-diagnosis due to high recurrence rates and therapeutic resistance. These challenges stem from the inability of conventional therapies to effectively penetrate the blood-brain barrier (BBB) and eradicate brain cancer stem cells (BCSCs), which drive tumor progression, recurrence, and resistance to treatment. To overcome these limitations, nanotechnology has emerged as a promising strategy. Brain-penetrating polymeric nanoparticles, particularly polyamidoamine (PAMAM) dendrimers [PAMAM-OH (G4)], offer enhanced biocompatibility, high surface functionality, and efficient penetration of the BBB due to their hydrophilic nature and small particle sizes. Metformin, a widely used antidiabetic medication, has demonstrated notable anticancer properties, including the inhibition of mitochondrial respiration and modulation of the AMPK/mTOR pathway, making it a compelling candidate for GBM therapy. In the present study, we synthesized and characterized a novel nano-formulation of metformin conjugated to the fourth-generation PAMAM dendrimer (P4-MET). This conjugate was evaluated for its pharmacokinetic profiles, safety, and therapeutic efficacy in treating GBM, both as a standalone treatment and in combination with brain radiotherapy (RT). The P4-MET formulation demonstrated superior pharmacokinetics, with prolonged retention in the tumor microenvironment and enhanced cytotoxicity against GBM cell lines compared with free metformin (f-MET). When combined with RT, the P4-MET conjugate synergistically improved therapeutic outcomes, significantly enhancing tumor cell death. Notably, the P4-MET formulation exhibited minimal systemic toxicity, confirming its safety for potential clinical applications. These findings suggest that P4-MET conjugates, with or without adjunctive radiotherapy, hold significant potential as a novel therapeutic approach for GBM.
]]></description>
<dc:creator><![CDATA[ Mahfooz, S., Wang, F., Chalbatani, G. M., Bronich, T. K., Romanova, S., Jia, y., Bhat, K., Zhang, K. ]]></dc:creator>
<dc:date>2026-05-15</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724405</dc:identifier>
<dc:title><![CDATA[Enhanced Radio-sensitization of Glioblastoma Using a Dendrimer-Based Metformin Nano-formulation through Direct Tumor Suppression and Indirect Immune Modulation]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.723724v1?rss=1">
<title>
<![CDATA[
Dual targeting of CCR2+ monocytes and neutrophils enhances anti-tumor immunity 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.723724v1?rss=1
</link>
<description><![CDATA[
Targeting immunosuppressive tumor-associated myeloid populations has emerged as a promising strategy to enhance anti-tumor immunity. The CCL2-CCR2 axis plays a central role in the recruitment of monocytes that differentiate into tumor-associated macrophages (TAMs), yet the therapeutic potential of CCR2 targeting remains limited. Using transgenic CCR2-DTR mice, we show that depletion of CCR2+ monocytes and TAMs reduced tumor growth across multiple models, accompanied by remodeling of the tumor microenvironment (TME). Residual CCR2-independent TAMs exhibited a pro-inflammatory and less immunosuppressive phenotype, and expressed the alternative recruitment receptor CCR3. Concomitantly, CCR2 depletion markedly enhanced anti-tumor immunity by increasing infiltration of activated CD8+ T cells. Splenocytes from tumor-bearing CCR2-DTR mice showed an increased IFN{gamma} response to a cancer-associated antigen. Furthermore, CCR2 depletion synergized with immune checkpoint blockade to enhance tumor control. Despite these effects, compensatory tumor infiltration of neutrophils following CCR2 targeting limited therapeutic benefit. These neutrophils exhibited a terminally differentiated, immunosuppressive phenotype and were associated with increased cancer cell-intrinsic expression of the neutrophil-recruiting chemokines Cxcl2 and Cxcl5. Importantly, combined depletion of CCR2+ cells and neutrophils overcame this resistance mechanism, resulting in reduced tumor growth, prolonged survival, and complete tumor clearance in 25% of the mice. Dual depletion of CCR2+ cells and neutrophils was also associated with a synergistic increase in circulating CD8+ T cells. These findings highlight the dynamic remodeling of the TME upon CCR2 depletion and suggest that combinatorial strategies addressing immunosuppressive neutrophil infiltration may improve the efficacy of CCR2 targeting therapies.
]]></description>
<dc:creator><![CDATA[ Fjaestad, K. Y., Johansen, A. Z., Linder, H., Carretta, M., Siersbaek, M., Baker, K. J., Thorseth, M.-L., Hübbe, M. L., Hald Andersen, M., Grontved, L., Madsen, D. H. ]]></dc:creator>
<dc:date>2026-05-15</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.723724</dc:identifier>
<dc:title><![CDATA[Dual targeting of CCR2+ monocytes and neutrophils enhances anti-tumor immunity]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.09.721157v1?rss=1">
<title>
<![CDATA[
Genomic, Clinical, and Spatial Predictors of Durable Response to BRAF/MEK Inhibition in BRAF-Mutant Melanoma 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.09.721157v1?rss=1
</link>
<description><![CDATA[
BRAF-targeted therapy (BRAFi/MEKi) and immune checkpoint blockade (anti-PD-1/anti- CTLA-4) have transformed the treatment of BRAF-mutant metastatic melanoma. While most patients who respond to targeted therapy eventually progress, a subset derives durable benefit, and biomarkers to identify this subset would inform optimal treatment selection. In this study, we analyzed pre-treatment tumor samples from a clinically annotated cohort of 155 patients with BRAF-mutant metastatic melanoma treated with first-line BRAFi/MEKi and followed for up to five years. We stratified patients into durable responders (PFS [&ge;] 24 months) and rapid progressors (PFS < 6 months with progression) and found that a global metric of tumor genomic heterogeneity, rather than individual gene alterations, distinguished these groups. Combining genomic heterogeneity with baseline tumor burden (e.g., lactate dehydrogenase (LDH) or radiographic lesion dimensions), we developed a parsimonious model that predicted durable responders with high precision and specificity. Notably, the analogous population of patients treated instead with immunotherapy were not durable responders, suggesting that the selected predictors of durable responders are targeted therapy specific. Spatial profiling of a subset of pretreatment biopsies (n = 47) demonstrated that high intratumoral, but not peritumoral, CD8+ T-cell infiltration correlated with prolonged survival on BRAF-targeted therapy and served as an independent predictive factor when considered with genomic heterogeneity and features of clinical tumor burden. Together, these findings highlight the distinct baseline intrinsic and extrinsic features underlying durable response to BRAF-targeted therapy and support their potential implication in guiding treatment selection for patients with BRAF-mutant metastatic melanoma.
]]></description>
<dc:creator><![CDATA[ Shi, Y., Savchenko, A., Brase, J. C., Reardon, B., Ricker, C. A., Park, J., Tarantino, G., Manos, M. P., Huang, A. Y., Van Allen, E. M., Garraway, L. A., Flaherty, K. T., Liu, D. ]]></dc:creator>
<dc:date>2026-05-15</dc:date>
<dc:identifier>doi:10.64898/2026.05.09.721157</dc:identifier>
<dc:title><![CDATA[Genomic, Clinical, and Spatial Predictors of Durable Response to BRAF/MEK Inhibition in BRAF-Mutant Melanoma]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724628v1?rss=1">
<title>
<![CDATA[
H3K27M-driven hypertranscription leads to a new targetable dependency in diffuse midline gliomas 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724628v1?rss=1
</link>
<description><![CDATA[
Diffuse midline gliomas (DMGs) are driven by the H3K27M oncohistone, a challenging therapeutic target. However, conventional therapeutic modalities are never curative. Against this backdrop, we address an important unresolved question--are there H3K27M-induced oncogenic vulnerabilities that can be exploited for therapeutic benefit. We show that H3K27M induces hypertranscription, thus identifying hypertranscription as a new molecular feature of H3K27M-driven DMGs. We demonstrate this finding in genetic mouse models, human DMG cells, and primary tumor specimens. We further demonstrate that H3K27M-induced hypertranscription perturbs replication, heightens basal replication stress, and enhances sensitivity to ATR inhibition. In exploring therapeutic implications of these findings, we document brain penetrance, target engagement, and therapeutic efficacy of a clinical-stage ATR inhibitor (alnodesertib) in vitro and in intracranial DMG xenografts. We further demonstrate synergistic activity of alnodesertib with radiotherapy, the current standard of care for DMGs. These findings provide the mechanistic underpinning and preclinical rationale for including alnodesertib as monotherapy and in combination with radiation in clinical trials for children with H3K27M DMGs. The broad implications of our studies highlight ATR inhibition as a therapy for aggressive human cancers displaying hypertranscription.
]]></description>
<dc:creator><![CDATA[ PAL, S., Wang, H., Geisberg, J., Mirza, T., Kohli, K., Nazaretian, A., Knowles, T., Graser, C. J., Bootz, K., Wojcikowska, O., Bartynska, M., Boulton, S. J., Majithiya, J. B., Robinson, H., Smith, G., Stiles, C., Chowdhury, D., Agar, N. Y. R., Mueller, S., Michor, F., Haas-Kogan, D. ]]></dc:creator>
<dc:date>2026-05-15</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724628</dc:identifier>
<dc:title><![CDATA[H3K27M-driven hypertranscription leads to a new targetable dependency in diffuse midline gliomas]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724407v1?rss=1">
<title>
<![CDATA[
Purinergic signaling promotes gliomagenesis through nuclear calcium transients 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724407v1?rss=1
</link>
<description><![CDATA[
Intracellular Ca2+ transients drive key developmental and physiological processes, yet their role in oncogenesis remains incompletely understood. In glioblastoma (GBM), an aggressive brain malignancy, tumor cellular networks exhibit self-sustaining Ca2+ transients that promote tumor growth through unclear mechanisms. Using patient-derived GBM models, we show that these transients depend primarily on intracellular Ca2+ stores and extend to the nucleus to drive tumorigenesis. A neuromodulator screen identified extracellular purines ATP and ADP as potent inducers of both nuclear and cytosolic Ca2+ transients via activation of metabotropic purinergic P2RY1 receptors, whose knockdown attenuates tumorigenicity in vitro and in vivo. Mechanistically, Ca2+ transients promote tumorigenesis via the nuclear Ca2+/calmodulin-dependent kinase CAMK4, which regulates transcriptional and epigenetic programs, as well as ribosomal DNA transcription. From the therapeutic perspective, pharmacologic P2RY1 inhibition suppresses tumor growth in vitro and in vivo. Collectively, these findings reveal a pharmacologically targetable oncogenic mechanism in GBM and possibly other malignancies.
]]></description>
<dc:creator><![CDATA[ Wang, S., Richter, J., Kim, C., Ronnen, R., Cai, J., Song, Y., Haddock, S., Stoessel, M., Dada, H., Gross, S., Guerrero, A., Karnavas, T., Stephan, G., Belizaire, G., Bonanni, L., Golub, D., Sabio, J., Schwarz, H., Jiang, A., Maleeha, N., Ghosh, A., Yung, M., Grossman-Glover, E., Tang, J., Gherghina, L., Donovan, A., Leonard, A., Chiriboga, L., Jones, D. R., Song, S. C., Mazzoni, E., Vincent, T., Schneider, R. J., Zagzag, D., Miura, Y., Basu, J., Brand, A. H., Placantonakis, D. G. ]]></dc:creator>
<dc:date>2026-05-15</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724407</dc:identifier>
<dc:title><![CDATA[Purinergic signaling promotes gliomagenesis through nuclear calcium transients]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.14.725216v1?rss=1">
<title>
<![CDATA[
Glutamatergic neuron-tumor synapses shape human glioblastoma cell states through radial glia plasticity 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.14.725216v1?rss=1
</link>
<description><![CDATA[
Glioblastoma (GBM) is a devastating primary brain tumor with remarkable inter- and intra-tumoral heterogeneity. GBM cells assume a spectrum of neurodevelopmental-like phenotypes and co-opt normal neurophysiological processes, which include synaptic integration with their neuronal microenvironment. This is mediated by neuron-tumor synapses (NTS) that predominantly involve glutamatergic receptors, which drive calcium elevations that promote tumor proliferation and invasion. The exact relationship between synaptic signaling and tumor cell fate specification, however, remains largely unexplored. Here, we develop and leverage a synapse-optimized human organoid tumor transplantation (so-HOTT) model of GBM to decipher how glutamatergic signaling impacts GBM lineage trajectories. so-HOTT preserves patient tumor heterogeneity, features excitatory NTS, and enables clonal lineage tracing of tumor cells after NTS perturbations. Genetic and pharmacological inhibition of AMPA and kainate receptors in so-HOTT shifts tumor cell composition from neuronal fates toward progenitor-proximal astrocytic/mesenchymal states. This occurs through the attenuation of calcium signaling and reduced plasticity of malignant radial glia (RG)-like progenitors, a previously unrecognized target of NTS. Through the integration of inputs from the neuronal microenvironment into glutamatergic signaling, progenitor populations modulate their transcriptional programs and cell fate, ultimately shaping GBM tumor heterogeneity. Targeting synaptic input may thus constrain the heterogeneity that fuels GBM adaptation and therapeutic escape.
]]></description>
<dc:creator><![CDATA[ Martija, A., Bristow, B. N., Rana, D., Bollu, S., Fazzari, E., Baisiwala, S., Nguyen, C. V., Ge, W., Kan, R. L., Azizad, D. J., Li, M. X., Nano, P. R., Cho, H., Perryman, T., Nathanson, D. A., Patel, K. S., Bhaduri, A. ]]></dc:creator>
<dc:date>2026-05-15</dc:date>
<dc:identifier>doi:10.64898/2026.05.14.725216</dc:identifier>
<dc:title><![CDATA[Glutamatergic neuron-tumor synapses shape human glioblastoma cell states through radial glia plasticity]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724508v1?rss=1">
<title>
<![CDATA[
Oncolytic measles virus reprograms the tumor microenvironment in a vascularized mesothelioma-on-chip model 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724508v1?rss=1
</link>
<description><![CDATA[
Pleural mesothelioma (PM) is a rare, aggressive cancer primarily caused by asbestos exposure and remains resistant to conventional chemotherapy. Although dual immune checkpoint inhibition (anti-PD-1/anti-CTLA-4) is now approved as first-line therapy, clinical benefit is limited to a small subset of patients, necessitating the need for alternative strategies. Oncolytic viruses (OVs) represent a promising approach as they selectively infect and lyse tumor cells while reprogramming the immunosuppressive tumor microenvironment (TME) into an immunostimulatory state. In PM, we previously showed that the attenuated Schwarz strain of measles virus (MV) oncolytic activity is mainly dependent on alterations in the type I interferon (IFN-I) pathway, rendering tumor cells sensitive to infection. Recently, we showed that monocytes/macrophages exposed to MV produce IFN-I, which protects PM cells via paracrine IFNAR signaling. This underscores the necessity of modeling the TME to accurately evaluate OV efficacy. Conventional rodent models are non-permissive to MV, and availability of fresh human PM tissue is scarce. We therefore developed a humanized 3D "vascularized mesothelioma-on-chip" (VMOC) model using microfluidic chips. It comprises two perfusable endothelial-lined parental vessels flanking a central secondary microvascular network (MVN), generated using human umbilical vein endothelial cells (HUVECs) embedded in fibrin and co-cultured alongside PM cells and primary human lung fibroblasts (hLFs). We characterized the integrity and functionality of the endothelial compartment as well as the cellular heterogeneity in VMOC using single-cell RNA sequencing. After administration of MV via the endothelial network, we observed infection and death of PM cells in addition to a strong activation of the type I interferon pathway and production of multiple inflammatory mediators. The VMOC model enables in vitro study of both MV infection and TME reprogramming, paving the way for a better understanding of the role of the TME in the response to treatment and for supporting the development of more personalized, targeted therapies for PM.
]]></description>
<dc:creator><![CDATA[ Rajkumari, N., Willems, M., Fresquet, J., Douillard, E., Devic, M., Perdrieau, H., Fradin, D., Fonteneau, J.-F., Boisgerault, N., Corre, I., Treps, L., van der Sanden, B., Blanquart, C. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724508</dc:identifier>
<dc:title><![CDATA[Oncolytic measles virus reprograms the tumor microenvironment in a vascularized mesothelioma-on-chip model]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724547v1?rss=1">
<title>
<![CDATA[
Pathway-Centric Integration of CRISPR Fitness with Molecular Features Draws Cancer State Maps 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724547v1?rss=1
</link>
<description><![CDATA[
Cancer cells display heterogeneous pathway activity that shapes therapeutic vulnerability, but mapping it remains challenging. Transcriptomic scores do not directly measure functional activity, and CRISPR knockout data alone lack molecular interpretability. We introduce StateMap, a pathway-centric framework integrating gene expression and genome-wide CRISPR knockout fitness data from the Cancer Dependency Map. For a given pathway, StateMap selects features by co-dependency and mutual information, then projects cell lines into a low-dimensional space reflecting pathway activity and molecular state. Applied to the Hippo pathway, it resolved five functional states refining the YAP-on/YAP-off dichotomy. Notably, the  Hippo-strong state showed selective dependence on integrin V{beta}5; ITGAV depletion triggered Hippo-dependent cell aggregation and G1 arrest via enhanced cell-cell adhesion. Machine learning transfer to TCGA identified a matching subtype with poor prognosis, nominated NNMT as a biomarker, and predicted sensitivity to the V inhibitor Cilengitide. StateMap enables pathway-specific state mapping and discovery of state-selective therapeutic vulnerabilities.
]]></description>
<dc:creator><![CDATA[ Hagiwara, T., Ito, K. K., Kuroki, K., Niikura, R., Hirota, M., Kawai, K., Uga, H., Iwakiri, J., Terai, G., Asai, K., Goyama, S., Shikata, S., Kanai, A., Suzuki, Y., Shimada, K., Fukuyama, M., Hata, S., Yamamoto, S., Chinen, T., Kitagawa, D. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724547</dc:identifier>
<dc:title><![CDATA[Pathway-Centric Integration of CRISPR Fitness with Molecular Features Draws Cancer State Maps]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724514v1?rss=1">
<title>
<![CDATA[
Cell line-dependent effects of spheroid formation method on drug response in melanoma models 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724514v1?rss=1
</link>
<description><![CDATA[
In this study, we evaluated the impact of different in vitro 3D culture modelling methods on the activity of doxorubicin (DOX) and 5-fluorouracil (5-FU) in human melanoma spheroids. Human melanoma A375 and IGR39 spheroids were generated using the hanging drop and non-adhesive surface methods. Spheroid growth dynamics were assessed by measuring changes in spheroid diameter. To compare the effects of anticancer drugs in spheroids of different sizes, spheroids of approximately 200 and 400 {micro}m were formed. Drug activity was evaluated based on spheroid growth and cell viability using the MTT assay. A375 spheroids formed using the non-adhesive surface method were more sensitive to DOX than spheroids formed using the hanging drop method. In smaller A375 spheroids, 10 {micro}M 5-FU reduced cell viability more effectively in spheroids formed using the hanging drop method. In contrast, IGR39 spheroids formed by the hanging drop method were more resistant than those formed on a non-adhesive surface. However, in IGR39 spheroids, the effects of DOX and 5-FU on growth and viability did not significantly differ between formation methods. In conclusion, A375 spheroid growth was not significantly influenced by the formation method, whereas IGR39 spheroid growth depended on the method used. A375 spheroids formed on non-adhesive surfaces were more sensitive to DOX, whereas 5-FU activity depended on drug concentration and spheroid size. In IGR39 spheroids, the effects of DOX and 5-FU on growth and viability were largely independent of the spheroid formation method. Based on these results, it can be concluded that the researchers should carefully select the spheroid formation method for their studies, as this may influence the results of the tested compounds effect on their size and viability.
]]></description>
<dc:creator><![CDATA[ Zilyte, A., Petrikaite, V. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724514</dc:identifier>
<dc:title><![CDATA[Cell line-dependent effects of spheroid formation method on drug response in melanoma models]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724428v1?rss=1">
<title>
<![CDATA[
Compact serum miRNA qPCR model for pancreatic cancer discrimination with independent and clinical validation 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724428v1?rss=1
</link>
<description><![CDATA[
BackgroundFor pancreatic cancer, practical blood-based tests for early detection and postoperative surveillance remain elusive. We sought to develop a qPCR-measurable serum microRNA (miRNA) panel that robustly discriminates pancreatic cancer from non-cancer controls and other malignancies.

MethodsWe profiled 255 serum miRNAs in batch 1 (n=72) and selected 27 candidates. Candidates were refined in batch 2 (n=552) and cross-batch evaluation was performed with batch 3 (n=391) to derive a miRNA model. Independent validation used batch 4 (n=616). Clinical relevance was assessed in an independent clinical cohort of resection patients with samples obtained preoperatively and at 1 and 12 months postoperatively.

ResultsThe miRNA model trained on batches 2 and 3 achieved an area under the curve (AUC) of 0.91 and 0.83 for pancreatic cancer versus non-cancer controls and non-cancer plus other cancers, respectively, when independently validated in batch 4. Stage-wise AUCs in batch 4 were 0.91 (I), 0.94 (II), 0.86 (III) and 0.90 (IV). In the clinical batch, the score decreased postoperatively (preoperative vs month 1; p<0.01) and was higher in recurrence than non-recurrence (p<0.001).

ConclusionsThe developed compact miRNA qPCR assay discriminated pancreatic cancer across independent assay batches and showed clinical relevance for postoperative surveillance.

Clinical Trial RegistrationNot applicable.
]]></description>
<dc:creator><![CDATA[ Yotsutsuji, S., Kataoka, H., Ando, T., Inada, M., Sugano, M., Takada, M., Esaki, M., Kato, K., Yamamoto, Y., Sano, Y. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724428</dc:identifier>
<dc:title><![CDATA[Compact serum miRNA qPCR model for pancreatic cancer discrimination with independent and clinical validation]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724432v1?rss=1">
<title>
<![CDATA[
Integrated spatial and single-cell transcriptomic analysis of aggressive glioblastoma growth dynamics. 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724432v1?rss=1
</link>
<description><![CDATA[
Glioblastoma (GBM) develops within a complex tumor ecosystem whose temporal dynamics remain poorly understood. Here, we performed longitudinal single-cell RNA sequencing and spatial transcriptomics across multiple timepoints in two widely used murine GBM models - CT2A and GL261 - which differ markedly in aggressiveness and response to immune checkpoint blockade. Tumor cell transcriptomes revealed model-specific programs: CT2A cells progressively upregulated epithelial-mesenchymal transition (EMT), non-classical MHC Class I, and progressively, hypoxia response pathways, resembling the human mesenchymal GBM cell state, while GL261 cells exhibited MHC Class II expression and developmental signatures resembling oligodendrocyte progenitor and astrocytic states. Ligand-receptor interaction analyses identified thrombospondins (Thbs1, Thbs2) and osteopontin (Spp1) as CT2A-specific tumor ligands mediating tumorigenic interactions with immune cells, with downstream targets enriched for EMT and TGF-{beta} pathways. Conversely, the GL261 model presented a differential potential to engage neuronal and perivascular guidance networks, with Glutamate and L1 cell adhesion molecule (L1cam) as lead signaling partners. The CT2A immune compartment exhibited progressive microglia-to-macrophage phenotypic conversion, enhanced macrophage infiltration driven by Spp1, and elevated T cell exhaustion, while GL261 maintained a distinct adaptive immune communication hub via MHC class II-CD4 signaling. Elevated THBS1, THBS2, and SPP1 expression correlated with poor survival in human GBM datasets. Together, these findings reveal divergent tumor-immune ecosystems in CT2A and GL261 that recapitulate distinct aspects of human GBM, with implications for therapeutic targeting.
]]></description>
<dc:creator><![CDATA[ Alves-Pereira, C. F., Kim, G. D., Sherpa, N., Colvin, K., Khan, S. M., Phan, K. P., Wang, A. Z., Dunn, I. F., Johanns, T., Tsitsykov, E., Desai, R., Dunn, G. P., Petti, A. A. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724432</dc:identifier>
<dc:title><![CDATA[Integrated spatial and single-cell transcriptomic analysis of aggressive glioblastoma growth dynamics.]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724415v1?rss=1">
<title>
<![CDATA[
FASN Inhibition Resensitizes Chordoma to Radiotherapy by Targeting Adaptive Unsaturated Fatty Acid Metabolism 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724415v1?rss=1
</link>
<description><![CDATA[
SUMMARYChordoma, a rare malignant notochordal tumor of the skull base and spine, is typically resistant to chemotherapy and radiotherapy and exhibits aggressive local recurrence. Here we show that chordoma recurrence correlates with a coordinated upregulation of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs), a low PFA/MUFA ratio and an adaptive, lipid peroxidation-resistant state that protects against DNA damage and cell death. Single-cell metabolic profiling identified a tumor subpopulation marked by a fatty acid biosynthesis-high state coupled to stemness. RT-tolerance was directly linked to elevated FASN and lipid droplet (LD) expansion, and MUFA-loading phenocopied RT-tolerance in chordoma cells. Mechanistically, LDs accumulated in response to RT via generation of ROS, and subsequent activation of ER-stress, SREBP1 and Fatty Acid Synthetase (FASN). DESI-MS showed that low-dose irradiation was sufficient to increase MUFAs early and build peroxidation resistant MUFA-LDs, whereas PUFA induction required a higher radiation dose. In a spatially defined manner in a patient-derived xenograft. Finally, in silico knockout and pharmacologic FASN blockade restored radiosensitivity and apoptosis in vitro and in vivo. Collectively, our result support a unifying model in which RT resistance in chordoma is shaped by an adaptive fatty acid metabolic program that buffers oxidative injury and increases survival of RT-resistant, stem-like tumor subpopulations. These findings further support FASN inhibition as a practical radiosensitization strategy for chordoma particulary where RT dose escalation is constrained by anatomy.

KEYPOINTSO_LIRecurrent chordoma exhibits fatty acid-associated metabolic reprogramming.
C_LIO_LIMUFA-associated lipid droplet accumulation is linked to radioresistance in chordoma cells.
C_LIO_LITargeting FASN restores radiotherapy sensitivity of chordoma in vitro and in vivo.
C_LI

IMPORTANCE OF STUDYThis study underscores the clinical importance of targeting metabolic vulnerabilities to restore radiosensitivity in chordoma. By integrating transcriptomics, metabolomics, and in vitro and in vivo models, we identified adaptive fatty acid metabolic reprogramming as a central mechanism of RT resistance in chordoma. Recurrent tumors were characterized by coordinated enrichment of unsaturated fatty acids, especially monounsaturated fatty acids (MUFAs), together with a low PUFA/MUFA ratio and a lipid peroxidation-resistant state. Mechanistically, RT-tolerance chordoma cells exhibited a high-FASN state driven by activation of the ROS-ER stress-PERK/SREBP1/FASN axis, leading to intracellular lipid droplet expansion. Importantly, genetic and pharmacologic inhibition of FASN restored radiosensitivity and enhanced apoptosis in both in vitro and in vivo models, suggesting a translatable therapeutic strategy. Together, these findings link adaptive metabolic reprogramming to RT resistance and support new therapeutic approaches for chordoma management.
]]></description>
<dc:creator><![CDATA[ WEI, R., Meng, Y., Nasajpour, E., Panovska, D., Oft, H. C. M., Xing, Y. L., Lee, C. K., Fernandez-Miranda, J. C., Banu, M. A., Zare, R. N., Petritsch, C. K. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724415</dc:identifier>
<dc:title><![CDATA[FASN Inhibition Resensitizes Chordoma to Radiotherapy by Targeting Adaptive Unsaturated Fatty Acid Metabolism]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724388v1?rss=1">
<title>
<![CDATA[
Integrated Collagen Architecture and Composition Improve Risk Stratification in Triple-Negative Breast Cancer 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724388v1?rss=1
</link>
<description><![CDATA[
PurposeTriple-negative breast cancer (TNBC) exhibits substantial clinical heterogeneity, with some patients experiencing early recurrence and poor survival despite similar clinicopathologic features. We sought to determine whether quantitative measures of intratumoral collagen architecture and composition derived from standard histopathologic specimens can identify patients at risk of recurrence and adverse survival outcomes.

Experimental DesignWe analyzed a retrospective cohort of 79 TNBC tumors assembled into a tissue microarray using a multimodal computational pathology framework integrating Massons Trichrome staining with COL1 and COL3 immunohistochemistry. Collagen architecture was quantified using fiber-based image analysis and unsupervised clustering, while collagen composition was assessed using a normalized COL3:COL1 ratio. Associations with recurrence-free interval (RFI) and overall survival (OS) were evaluated using Kaplan-Meier analysis, restricted mean survival time (RMST), and Cox proportional hazards modeling.

ResultsUnsupervised analysis identified four distinct collagen architectural states, which were consolidated into low-risk and high-risk groups based on recurrence patterns. High-risk collagen architecture was associated with significantly worse long-term RFI (log-rank p=0.025; RMST difference 10.1 months). Independently, a higher COL3:COL1 ratio was associated with improved OS (log-rank p=0.042; RMST difference 9.4 months). Integration of architectural and compositional biomarkers further refined risk stratification, identifying a subgroup with high-risk architecture and low COL3:COL1 ratio that exhibited the poorest survival outcomes. Notably, collagen-based stratification identified patients with divergent outcomes not readily predicted from tumor stage alone.

ConclusionsQuantitative assessment of intratumoral collagen architecture and composition provides clinically meaningful prognostic information in TNBC and enables stratification of recurrence and survival risk. These findings support extracellular matrix phenotyping as a practical and scalable computational pathology approach for refining risk assessment in TNBC.

Translational RelevanceTriple-negative breast cancer (TNBC) remains clinically challenging due to heterogeneous outcomes that are not fully captured by standard clinicopathologic variables. In this study, we demonstrate that quantitative features of intratumoral collagen architecture and composition, derived from routine pathology specimens, provide clinically meaningful prognostic information. Collagen-based biomarkers, including distinct collagen architectural phenotypes and the COL3:COL1 ratio, identify patient subgroups with distinct recurrence and survival outcomes, particularly among individuals whose risk is not adequately predicted by conventional staging. Importantly, these features can be extracted from widely available histological stains and immunohistochemistry, supporting the potential integration into existing pathology workflows. These findings support the tumor microenvironment as an underutilized source of biomarkers and suggest that extracellular matrix-based phenotyping may improve risk stratification and inform clinical decision-making in TNBC.
]]></description>
<dc:creator><![CDATA[ Ozbilgic, R., Dinc, B., Vipparthi, K., Seachrist, D., Nicolas, M., Keri, R. A., Liu, X., Yildirim, M., Karaayvaz, M. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724388</dc:identifier>
<dc:title><![CDATA[Integrated Collagen Architecture and Composition Improve Risk Stratification in Triple-Negative Breast Cancer]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724216v1?rss=1">
<title>
<![CDATA[
Functional T cells trapped behind a stromal wall: a Brake-with-Wall phenotype redefines pancreatic adenocarcinoma immunotherapy resistance 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724216v1?rss=1
</link>
<description><![CDATA[
BackgroundPancreatic ductal adenocarcinoma (PDAC) is the paradigmatic immunotherapy-refractory cancer, with a 5-year survival of approximately 12% and minimal benefit from immune checkpoint blockade (ICB). The dominant mechanistic explanation classifies PDAC as a T cell-excluded "cold" tumor, implying that no functional anti-tumor T cells are available for checkpoint release. Whether this Block-strategy view is correct has not been re-examined under integrated evasion-framework analysis.

MethodsWe applied a previously developed 16-module immune evasion framework to TCGA-PAAD (n=183), integrated with hub-cytokine analysis (IL-10/TGF-{beta}), Kv1.3-immune channelome data, and clinical trial mapping (12,007 trials). Single-cell validation used two independent PDAC cohorts retrieved through TISCH2: PAAD_CRA001160 (Peng 2019, 35 samples [24 PDAC + 11 adjacent normal], 57,443 cells) and PAAD_GSE154778 (Lin 2020, 16 samples, 14,953 cells), examined for CD8A, TOX, PRF1, KCNA3, and FAP expression by cell type.

ResultsPDAC scored highest in CAF Wall (z=0.768) and Platelet Cloak (z=0.663) modules; strategy classification yielded Brake -- not Block -- driven by a positive KCNA3-survival relationship (HR=0.649, 95% CI 0.43-0.97, p=0.037). Single-cell qualitative analysis of TISCH2 violin plots showed that CD8 exhausted T cells (CD8Tex) carried (i) high CD8A, (ii) the highest TOX expression among annotated cell types, (iii) preserved PRF1, and (iv) high KCNA3 expression. FAP was strongly localized to fibroblasts (peak [~]3.0 vs. <0.5 elsewhere). The pattern was reproduced in the second cohort. The optimal three-module attack (MHC restoration + CAF disruption + VEGF blockade) suppressed 10 of 16 evasion modules in silico (62.5%); zero of 370 PDAC immunotherapy trials test this combination.

ConclusionsPDAC may not be T cell-cold but T cell-trapped: CD8 T cells with intact Kv1.3 channels appear immobilized behind a FAP-positive cancer-associated fibroblast wall. ICB monotherapy is mechanistically insufficient because the brake is engaged on T cells that cannot reach the tumor. The framework predicts that triple-targeted intervention -- checkpoint release + CAF wall disruption + vascular normalization -- is the minimum effective strategy. This is a hypothesis-generating computational analysis; prospective experimental and clinical validation are required.
]]></description>
<dc:creator><![CDATA[ Yong, J. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724216</dc:identifier>
<dc:title><![CDATA[Functional T cells trapped behind a stromal wall: a Brake-with-Wall phenotype redefines pancreatic adenocarcinoma immunotherapy resistance]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724004v1?rss=1">
<title>
<![CDATA[
The miR-221-5p/RAD18/RAD51 axis regulates DNA damage tolerance and homologous recombination to drive platinum resistance in ovarian cancer. 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724004v1?rss=1
</link>
<description><![CDATA[
Platinum resistance remains a major barrier in Ovarian cancer (OC) treatment[1]. While hyperactivation of DNA damage response (DDR) is a hallmark of chemoresistance[2], the underlying epigenetic mechanisms driving this adaptation remain poorly understood. Here, we identify a novel post-transcriptional regulatory axis involving miR-221-5p that governs two critical DDR effectors: RAD18, which mediates DNA damage tolerance through trans-lesion synthesis (TLS)[3][4], and RAD51, the central recombinase for homologous recombination (HR)[5][6]. Although the miR-221/222 cluster is traditionally categorized as oncogenic[7][8], we demonstrate that the miR-221-5p arm functions as a potent tumor suppressor in OC. Bioinformatic and luciferase reporter assays confirmed that miR-221-5p directly targets the 3'UTRs of both RAD18 and RAD51. In OC clinical specimens and cell lines, miR-221-5p downregulation inversely correlates with RAD18/RAD51 expression. Functionally, miR-221-5p restoration suppressed platinum-induced PCNA mono-ubiquitination and HR, inducing a "functional BRCAness" that sensitized both established and patient-derived primary OC cells to carboplatin and PARP inhibition. Furthermore, in vivo disseminated xenograft models demonstrated that stable miR-221-5p expression significantly reduced tumor burden. Collectively, our results delineate a novel regulatory mechanism where loss of miR-221-5p drives chemoresistance by derepressing the RAD18/RAD51 axis, identifying this axis as a promising therapeutic target.
]]></description>
<dc:creator><![CDATA[ Omy, T. R., Sah, N., Kairamkonda, S., Mani, C., Islam, M. A., Reedy, M. B., Palle, K. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724004</dc:identifier>
<dc:title><![CDATA[The miR-221-5p/RAD18/RAD51 axis regulates DNA damage tolerance and homologous recombination to drive platinum resistance in ovarian cancer.]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
</rdf:RDF>
