Skip to content

#预印本

Today 0 items
Oct 15Thu
  1. biorxiv.org49

    Pervasive expression of early embryonic programs in cancer has stage-dependent survival impact

    Early embryonic gene expression programs are widespread in human tumours, and transcriptional similarity to distinct preimplantation stages independently predicts overall survival beyond age, sex, mutational status and molecular subtype. Similarity to zygote and 2-cell embryo stages predicted improved survival, driven in kidney cancer by stromal and immune cells, while trophectoderm-associated programs in tumour cells predicted worse survival in breast cancer and melanoma and were linked to MYBL2 and FOXM1 dependencies.

  2. biorxiv.org42

    Tobacco Carcinogen Induces Persistent DNA Damage and Homologous Recombination Dysregulation in Pancreatic Ductal Carcinogenesis

    The tobacco carcinogen NNK produces a biphasic DNA damage response in human pancreatic ductal epithelial cells: 5 days of exposure induced double-strand breaks with ATM-γH2AX activation and RAD51/BRCA2 recruitment, while 50 days caused persistent damage signaling, upregulation of HR genes (RAD51, BRCA1, BRCA2, FANCD2, PLK1), altered RAD51 localization, and chromosomal instability. In human PDAC tissue microarrays and TCGA-PAAD data, increased γH2AX correlated with tumor progression and poor overall survival, and elevated RAD51 with adverse outcomes, positioning γH2AX as a candidate prognostic biomarker in tobacco-associated PDAC.

  3. biorxiv.org61

    A microbiota-driven neuroepithelial feed-forward circuit drives gastroesophageal junction tumorigenesis

    Bile acid remodeling enriches the oral commensal Prevotella melaninogenica at the gastroesophageal junction, where bacterial succinate activates vagal sensory neurons and SUCNR1-expressing tuft cells. Tuft cells release 15-d-PGJ2 to sensitize sensory neurons, while neuronal CGRP drives expansion and tuft-cell differentiation of neuro-responsive epithelial progenitors through RAMP1, forming a self-reinforcing microbiota-neuron-epithelium circuit that promotes dysplastic progression. Genetic or pharmacological disruption of the circuit, including with the approved CGRP antagonist rimegepant, suppresses tumor development.

  4. biorxiv.org49

    NIK stabilization reprograms the pancreas toward chronic pancreatitis and pancreatic lipomatosis

    Sustained stabilization of NF-κB-inducing kinase (NIK) in a pancreas-specific mouse model triggered fully penetrant remodeling, with acinar cell death by the end of the first week of age, acinar-to-ductal metaplasia, organ atrophy, and extensive adipose replacement. Deep learning on spatial transcriptomics showed progressive loss of acinar identity and identified GPA33 as a surface marker of ADMs. Relb deletion fully rescued the phenotype, placing RelB-dependent non-canonical NF-κB signaling upstream of chronic pancreatitis and pancreatic lipomatosis.

  5. medrxiv.org40

    Choroid plexus asymmetry on routine MRI as an imaging signature of breast cancer brain metastasis

    Choroid plexus asymmetry on routine contrast-enhanced brain MRI is associated with breast cancer brain metastasis. In 1,000 women with breast cancer, 190 with brain metastasis, a deep-learning-derived Choroid Plexus Asymmetry Index was elevated in metastasis cases (median 0.088 vs 0.059; adjusted OR 1.58 per +1 SD, 95% CI 1.32-1.88), independent of peripheral inflammation markers, histological grade, tumour laterality and metastasis side. Total choroid plexus volume did not differ between groups, pointing to asymmetry rather than size as the relevant signature.

  6. biorxiv.org58

    Dissection of Polycomb complexes reveals canonical PRC1-independent 3D chromatin interactions

    Polycomb-mediated 3D chromatin interactions persist even when canonical Polycomb repressive complex 1 (cPRC1) is depleted, contradicting existing models that place cPRC1 at the center of this process. Using Polycomb subunit degrons combined with Region Capture Micro-C, ChIP-seq, nascent transcriptomics, and live-cell imaging, the authors show that within cPRC1, polyhomeotic proteins are the main contributors to interactions, and that the residual interactions do not depend on any single variant PRC1 or PRC2 complex. The work raises the possibility of a more general, cPRC1-independent mechanism for Polycomb-mediated interactions.

  7. biorxiv.org49

    AMPK Signalling Rewires WWP1 mediated RUNX1 Ubiquitination in CML Progression

    The E3 ubiquitin ligase WWP1 binds the PPxY motif of RUNX1 and catalyzes K63-linked polyubiquitination that stabilizes the protein and drives chronic myeloid leukemia cell growth. AMPK phosphorylates WWP1 at Thr692, sending it to lysosomal degradation, and also phosphorylates RUNX1 to curb its leukemogenic activity. Metformin activated this AMPK-WWP1-RUNX1 axis in leukemia cell lines, primary CML patient-derived cells, and xenograft tumors, pointing to WWP1 as a therapeutic vulnerability.

  8. biorxiv.org40

    A Multi-Kinase Inhibitor Screen Identifies mTOR Signaling as a Vulnerability in Advanced Prostate Cancer.

    Loss of the receptor tyrosine kinase AXL is linked to treatment resistance, aggressive phenotypes, and shorter overall survival in prostate cancer. Screening isogenic CRISPR-generated AXL-knockout cells against 1,814 kinase inhibitors identified Torin-2, which showed an ~18-fold lower IC50 in AXL-knockout than AXL-wildtype cells. PRISM/DepMap analysis confirmed a selective vulnerability to PI3K/AKT/mTOR pathway inhibition, pointing to mTOR inhibition as a therapeutic strategy for AXL-deficient prostate cancer.

  9. biorxiv.org42

    Spatial Tumour Tissue Distribution Dynamics of a Bicycle Peptide-MMAE Toxin Conjugate Profiled by Targeted Mass Spectrometry

    Laser capture microdissection coupled to targeted LC-PRM mass spectrometry maps the spatial distribution of MMAE released from the NECTIN-4-binding Bicycle Drug Conjugate zelenectide pevedotin (BT8009) at sub-tissue resolution in mice. The method showed progressive accumulation and sustained retention of MMAE in tumour tissues over 24 h, while levels in plasma, liver and muscle declined after early exposure, and revealed heterogeneous MMAE distribution between tumour cell-rich and stroma-rich regions with distinct temporal patterns.

  10. biorxiv.org54

    Transcriptomic and phenotypic characterization of Alzheimer's disease risk genes in neurons and astrocytes highlights shared and cell type specific cellular mechanisms

    Knockouts of roughly 250 candidate Alzheimer's disease genes in iPSC-derived iNeurons and iAstrocytes show highly cell-type-specific effects that converge on shared pathways. Disease-linked expression programs from postmortem patient samples responded to the knockouts, and phenotypic analyses profiled each gene. The screen identified CCDC6 roles in cell cycle and activation state in iAstrocytes and C2orf49 regulation of endoplasmic reticulum stress responses in iNeurons.

Oct 14Wed
  1. biorxiv.org52

    Co-targeting KRAS and BCL-2 induces pyroptosis and antitumor tertiary lymphoid structures

    Co-targeting KRAS and BCL-2 synergistically triggers GSDME-mediated pyroptosis in KRAS G12D-mutant lung tumors, which are metabolically vulnerable through weakened HK1 interaction and reduced spare respiratory capacity compared with G12C. The combination induces functional tertiary lymphoid structures in vivo, and depletion experiments show the antitumor efficacy depends on B cells. It also drives membrane attack complex deposition in situ and elicits memory antitumor responses.

  2. biorxiv.org40

    Early-onset spontaneous murine mammary tumors show increased lymphocyte representation and reduced MHC antigen presentation

    A wild-derived PWK/PhJ genetic background accelerates HER2/neu-driven mammary tumor onset and reshapes the tumor immune microenvironment. (BALBxPWK) F1 NeuT females developed tumors at 10 weeks versus 15 weeks in BALB NeuT mice (p < 0.0001), with more tumor-infiltrating T and B cells but lower expression of cytotoxicity genes Tox, Ltk, Nkg7, and Gzmb. Proteomics found coordinate down-regulation of Stat1, Tapbp, Parp9, and Dtx3l with MHC class I and II proteins, indicating that inherited background, not the oncogene alone, governs antigen presentation and immune recognition in these tumors.

  3. biorxiv.org52

    Microglia-derived Small Extracellular Vesicles Promote Bone Marrow Monocyte Expansion and Recruitment in Glioblastoma.

    Tumor-associated microglia in glioblastoma release small extracellular vesicles that traffic to the bone marrow, where they selectively target monocytes and their progenitors. Internalization of these vesicles activates MAPK signaling and inflammatory transcriptional programs, driving differentiation and expansion of inflammatory monocytes that are then recruited into the tumor microenvironment. The work identifies a communication route between the glioblastoma TME and the peripheral immune system that helps establish the immunosuppressive TME driving GBM progression.

  4. biorxiv.org52

    Trp53 heterozygosity defines novel states impacting tumor plasticity and progression in Kras-initiated non-small cell lung cancer

    Trp53 single-allele loss expands transcriptional plasticity and increases genomic instability relative to complete Trp53 loss in KrasG12D-driven murine lung tumors, while K and KP+/- mice live longer than KP mice, matching clinical survival patterns. Murine KP+/- signatures and copy-number profiles appear in human NSCLC datasets, and two signatures correlate with better and worse patient survival, respectively. TP53 heterozygosity therefore defines a distinct genomic landscape that should inform therapeutic strategy in KRAS-mutant lung cancer.

  5. biorxiv.org48

    Oncogenic ETS factors expressed from fusion genes utilize EWSR1 to associate with the paraspeckle and regulate transcription.

    Oncogenic ETS fusion proteins ERG and EWSR1::FLI1 associate with the paraspeckle scaffold long non-coding RNA NEAT1_2, linking them to this EWSR1-containing nuclear organelle. Disrupting paraspeckles in prostate cancer and Ewing sarcoma cell lines disrupted oncogenic phenotypes and, in Ewing sarcoma cells, produced transcriptional profiles similar to loss of EWSR1::FLI1. The work identifies the paraspeckle as a transcriptional regulator and potential drug target in ETS fusion cancers.

  6. biorxiv.org45

    A multimodal precision oncology platform integrating genomics,single-cell transcriptomics, and functional drug screening expandstherapeutic options in pediatric brain tumors

    A tiered precision oncology framework combining deep whole-genome sequencing, single-cell RNA sequencing, and ex vivo functional drug screening was applied to 17 children with malignant CNS tumors. Functional screening gave every patient at least one high-confidence targeted-therapy or chemotherapy nomination, single-cell RNA sequencing found an average of 37 druggable gene targets per patient, and high-confidence targeted-therapy recommendations rose fourfold. Functional classifications matched outcomes in 8 of 10 evaluable cases.

  7. biorxiv.org50

    Biomarker-driven and gene-enhanced viral therapy for malignant peripheral nerve sheath tumor

    Loss of the PRC2 histone mark H3K27me3, common in high-grade MPNST, sensitizes tumors to the oncolytic HSV G47Δ, but also triggers a compensatory integrated stress response that blunts viral protein translation. Engineers built G47Δ² with tumor-regulated ICP34.5 expression (BIRC5-driven), limiting daily xenograft tumor-volume growth to 0.6% (95% CI -2.9–4.2%) versus 8.3% for G47Δ² and 22.5% for controls, though murine gastrointestinal toxicity reduced event-free survival.

  8. biorxiv.org40

    Predicting resistance to synthetic lethal therapies in cancer

    Resistance to synthetic lethal cancer therapies can be predicted from molecular network features. A random forest model combining protein-protein interaction, co-expression and essentiality data, trained on CRISPR-Cas9 resistance screens across ten SL biomarker-target pairs, achieved a mean AUROC of 0.72 under leave-one-SL-pair-out validation (range 0.57-0.91) and independently predicted resistance to the MTAP-PRMT5 and ATM-ATR therapies now in trials. The work gives a computational way to anticipate resistance mechanisms before they emerge.

  9. medrxiv.org41

    MRI Biomarkers for Brain Metastases in Lung Cancer Using Machine Learning

    MRI-derived radiomic features improved prognostic stratification beyond clinical variables in 103 patients with brain metastases from lung cancer. The combined clinical-imaging DeepSurv model reached a concordance index of 0.728 for overall survival, and risk groups separated median overall survival at 26.7 versus 9.1 months. Imaging-only high-risk patients were less likely to have tumor-infiltrating lymphocytes and PD-L1 expression of at least 50%, linking the biomarkers to the tumor immune microenvironment.

  10. biorxiv.org57

    An RFX-driven ciliogenic cell state defines ex vivo FGFR-inhibitor sensitivity in colorectal cancer

    An RFX-driven ciliogenic cell state marked by upregulation of cilia-related genes predicts selective sensitivity to the FGFR inhibitor erdafitinib in colorectal cancer. Image-based ex vivo drug profiling with matched transcriptomics of 127 patient biopsies linked the signature to poor progression-free survival (hazard ratio 2.28; adjusted p=0.0098), even in early-stage disease, and knockdown of RFX2 and RFX3 attenuated erdafitinib sensitivity. The work offers a patient-stratified route to FGFR inhibition beyond current CRC treatment paradigms.

  11. biorxiv.org47

    Tumour-derived factors prime microglia for immune checkpoint-mediated T-cell regulation

    Soluble tumour-derived factors, not direct tumour contact, drive early microglial activation: quantitative proteomics showed extensive remodelling of the microglial proteome after exposure to tumour-conditioned media, with coordinated upregulation of MHC-I, PD-L1 and Galectin-9. Flow cytometry in murine and human cell models confirmed increased PD-L1 and MHC-I, and these microglia induced PD-1 and TIM-3 on cocultured T-cells. Single-cell RNA sequencing datasets from brain tumour patients recapitulate the same immune-regulatory program.

  12. biorxiv.org58

    Catabolism of extracellular glutathione is a driver of metastasis formation

    Cancer cells forming liver metastases can catabolize extracellular glutathione via gamma-glutamyl-transferase to obtain cysteine, sustaining proliferation and preventing ferroptosis when cystine is absent from the liver microenvironment. The mechanism was independent of system Xc- but required glutamate-cysteine ligase activity. GGT1 expression correlated with poor survival and was upregulated in liver metastases of human breast cancer patients, and Ggt1 overexpression in murine breast cancer cells enhanced liver colonization and lung metastases after orthotopic implantation.

    Why it matters: It identifies extracellular glutathione catabolism via GGT as a mechanism driving metastatic colonization of cystine-poor organs.

  13. biorxiv.org46

    THERAPY RESISTANCE IN MELANOMA DRIVES CILIOGENESIS AND GLUTAMINE/ASPARTATE METABOLISM DEPENDENCY

    Drug resistance in BRAF melanoma enhances primary ciliogenesis, and this cilia formation is required for cells to respond and survive combination therapy. Using in vitro and in vivo models of target therapy resistance, the authors identified a translational program supporting ciliogenesis in resistant melanoma. Knocking out IFT88 to impair cilia formation rewired glutamine and aspartate metabolism, defining a metabolic mechanism underlying therapy resistance.

  14. biorxiv.org53

    FLASH X-rays preserve neutrophil chromatin to boost antitumor immunity

    FLASH X-rays at 8 Gy, unlike an equal conventional dose-rate dose, triggered a robust abscopal antitumor effect with anti-PD-1 in a bilateral subcutaneous tumor model in mice. The ultrashort dose delivery conserved neutrophil chromatin compaction, inhibiting neutrophil extracellular trap formation and reversing NET-mediated CD8+ T-cell exclusion, while conventional or split-dose FLASH caused chromatin hyper-relaxation and NETosis. Radiation-induced chromatin relaxation in neutrophils emerges as a determinant of radioimmunotherapy outcome.

  15. biorxiv.org45

    Cyclic Hypoxia drives Wnt5a-ROR1 stroma-tumor crosstalk promoting breast cancer growth

    Cyclic hypoxia, unlike stable hypoxia, reprograms the triple-negative breast cancer microenvironment in a cell type specific way: it reverses chronic hypoxia-induced cell cycle arrest and a stabilized WNT5A+/COL6+ mesenchymal subpopulation, activates fibroblasts, and suppresses MSC proliferation. Single cell RNA and ATAC sequencing of a multicellular TNBC co-culture traced the effect to paracrine WNT5A/B-ROR1 signaling between fibroblasts and cancer cells. Blocking this crosstalk in a mouse CAF-TNBC co-xenograft model reduced tumor growth in vivo.

  16. biorxiv.org50

    PIEZO1 marks a low neuroendocrine state and supports cisplatin tolerance in small cell lung cancer

    PIEZO1 marks a low neuroendocrine cell state and supports cisplatin tolerance in small cell lung cancer. Its upregulation accompanied loss of NE markers in chemoresistant H69AR cells, with reduced cisplatin sensitivity in H446DDP cells, and patient multiomics, single-cell and spatial data linked PIEZO1 to low NE activity. PIEZO1 depletion lowered cisplatin IC50 and raised drug-induced apoptosis, while Yoda1 increased calcium signals and cisplatin tolerance, supporting an actomyosin-YAP-linked mechanism.

  17. biorxiv.org63

    Glyceraldehyde-3-phosphate sensing by SOS1 and RAS sustains a self-reinforcing oncogenic metabolic-signaling circuit

    The glycolytic intermediate glyceraldehyde-3-phosphate (GA3P) directly binds SOS1 and RAS, enhancing their interaction and sustaining hyperactivated RAS signaling in RAS-mutant cancer cells. GA3P accumulates through MAZ-dependent transcriptional upregulation of GLUT6, an atypical class III glucose transporter. Suppressing MAZ or GLUT6 selectively inhibits RAS-mutant cancer cells in vitro and in vivo, and GLUT6 expression is elevated in clinical RAS-mutant human malignancies.

    Why it matters: Identifies GA3P-SOS1-RAS as a metabolic activation loop and MAZ-GLUT6 as a synthetic-lethal target in RAS-mutant cancers.

  18. biorxiv.org51

    CCR2 is a potential biomarker and therapeutic target in Group 3 medulloblastoma

    High CCR2 expression correlates with dissemination and reduced survival in Group 3 medulloblastoma, across 1094 primary tumor samples, and CCR2 protein rises in recurrent/metastatic tumors versus paired primaries. Overexpression of CCR2 in ONS76 and UW228 cells drove proliferation and migration, and CCR2-driven mouse xenografts showed aggressive disease and decreased survival. The CCR2 antagonist Cenicriviroc suppressed CCR2-mediated signaling and showed therapeutic efficacy against established tumors in vivo.

  19. biorxiv.org50

    Sexual reproduction impacts vertebrate organ aging

    Lifelong mating reshapes organ aging in killifish, a new vertebrate model for the question. In old female livers, mating dampened hepatocyte inflammation, reduced myeloid cell levels, and machine-learning models predicted a 'younger' transcriptomic age in several liver cell types; mating also reduced hepatic lipid accumulation and improved resilience to acetaminophen. In publicly available human datasets, sexual experience associated with a 'younger' plasma proteomic age of several cell types, including hepatocytes.

  20. biorxiv.org41

    Spatial transcriptomics reveals interferon pathway enrichment in early relapsing serous carcinoma

    Spatial transcriptomics of matched treatment-naive adnexal and omental tumors from nine high-grade serous carcinoma patients found that short platinum-free interval tumors show an interferon-driven inflammatory phenotype at both sites. C3, IFI27 and BST2 were consistently associated with short PFI across sites and validated by RNA in-situ hybridization; in two public ovarian cancer cohorts, high C3 expression was significantly associated with shorter platinum-free survival. The work nominates C3 as a candidate prognostic biomarker and potential therapeutic target.

  21. medrxiv.org52

    Beyond ERBB2 amplification: RNA and proteomic HER2 assessment for pan-tumor treatment stratification

    RNA-based and proteomic HER2 screening identified HER2-enriched tumors beyond ERBB2 amplification in a pan-tumor cohort of 1,331 biopsies, with validation in 3,898 external biopsies. All six objective responses among 51 treated patients occurred in tumors positive by ERBB2 mRNA and the combined RNA-signature. ERBB2 mRNA positivity was linked to longer time on treatment (hazard ratio 0.42) and overall survival (0.41), supporting prospective evaluation for treatment selection.

  22. biorxiv.org43

    p53 activity links chromosomal instability to pro-migratory extracellular vesicles

    Acute chromosomal instability in p53-proficient NIH/3T3 cells splits cells into two p21-RFP populations with distinct fates: p21-RFPLOW cells re-enter the cell cycle after short arrest, while p21-RFPHIGH cells show persistent arrest with a senescence-like state. Late-stage p21-RFPHIGH-derived extracellular vesicles are enriched for ECM-, adhesion-, and cytoskeleton-associated proteins and confer increased migration on recipient cells, linking p53 activity to pro-migratory paracrine signaling.

Oct 13Tue
  1. biorxiv.org52

    Cross-species analysis identifies APOBEC3-associated spliceosomal snRNA hypermutability

    Hypermutability of spliceosomal snRNA genes is concentrated in RNA polymerase II-transcribed snRNA genes and is strong in primates but much weaker in rodents and chicken, matching lineage differences in APOBEC3 repertoires. Human Pol II-transcribed snRNA genes show mutational strand asymmetry, APOBEC3-associated mutational signatures and strong APOBEC3B binding. R-loops are frequent even in mouse genes with weak hypermutability, so R-loop formation alone cannot explain the phenotype.

  2. biorxiv.org51

    Spatial context of cellular heterogeneity in triple-negative breast cancer reveals actionable subtypes

    Bulk and spatial transcriptomics with cellular mapping of breast tissue from a large patient cohort identified three reproducible TNBC ecosystem subtypes with distinct spatial tumor-microenvironment architectures and treatment-response phenotypes: an immune-exhausted subtype associated with immune checkpoint therapy, a fibrotic/hypoxic subtype, and a metabolically reprogrammed subtype driven by nuclear-receptor and fatty-acid signaling. Multiplexed imaging independently confirmed the immune-infiltrated versus stromal-excluded architectures, and subtype-specific markers offer a basis for subtyping and candidate therapeutic vulnerabilities.

  3. biorxiv.org49

    Spatially resolved tumor-microenvironment architecture defines therapeutic response in unresectable hepatoblastoma

    Spatially organized tumor-microenvironment architecture distinguishes clinical outcomes in unresectable hepatoblastoma. Spatial transcriptomics (10x Visium, n = 11 tumors) and single-cell spatial imaging (NanoString CosMx, n = 3 tumors) on post-chemotherapy explants identified three architectures: relapse-prone tumors showed centralized, TME-dominated organization with SPP1+ TAMs, CAFs, hypoxia and MDK-LRP1 signaling, while non-relapse tumors showed compartmentalized tumor-immune interactions and preserved epithelial differentiation. Spatial architecture, not composition alone, may explain variable response beyond current risk stratification.

  4. biorxiv.org44

    Pan-cancer remodeling of reactive oxygen species homeostasis: distinct roles of the ROS-generation and antioxidant arms in immune context and outcome

    Pan-cancer analysis of a 107-gene ROS program shows both ROS-generation and antioxidant arms are coordinately up-regulated in tumors, but carry distinct meanings. The composite balance score tracked reduced immune infiltration, driven by low generation-arm activity in immune-cold tumors, while adverse outcome was attributable to the antioxidant arm and generation was null. In cohort-held-out validation, redox programs outperformed generic programs in separating tumors from adjacent normal tissue across cancer types.

  5. medrxiv.org48

    Methylation-defined tumour subgroups guide recognition of genetic predisposition in Wilms tumour

    DNA methylation profiling of 138 Wilms tumours identified five molecular clusters that capture predisposition-associated heterogeneity, including a distinct WT1-driven subgroup. Cluster-guided reanalysis uncovered previously unrecognised WT1 pathogenic variants, one of which led to surveillance enrolment, and a random forest classifier predicted WT1-driven tumours with ~90% accuracy in independent validation cohorts. Tumour methylation profiling can thus guide targeted variant reanalysis and reveal germline variants missed by standard diagnostics.

    Why it matters: Because it shows tumour methylation can flag germline predisposition that standard diagnostic workflows miss.

  6. biorxiv.org44

    Radiotherapy Reshapes the 3D Genome in Medulloblastoma Cells

    A single 2 Gy dose reorganized the 3D genome and rewired transcription and protein expression in ONS-76 medulloblastoma cells, shifting chromatin towards active A compartments, forming new TAD boundaries, and transiently strengthening existing ones while global genome organisation stayed stable. Integrated RNA-seq, proteomics, and Micro-C pointed to LAMB3 and AKR1B10 as candidate mediators of radioresponse that stayed elevated after fractionated irradiation. This is the first genome-wide picture of radiation-induced chromatin reorganisation in a medulloblastoma model.

    Why it matters: It gives the first genome-wide map of how clinically relevant radiation remodels 3D chromatin in medulloblastoma cells.

  7. biorxiv.org40

    Positive selection and structural disruption of KCNA5 by mutation in colorectal cancer

    KCNA5 (Kv1.5) emerges as the potassium channel under the strongest positive mutational selection in colorectal adenocarcinoma, identified by a dN/dS screen of 16 potassium channels expressed in the large intestine. Mutations cluster in the T1 tetramerisation, S1-S4 voltage-sensor and pore domains while avoiding the selectivity filter, and computational analyses of D166N and G128R predict structural disruption. KCNA5-mutant tumours show reduced expression of cell-cycle, KRAS-related and inflammatory pathways, effects not reproduced by low KCNA5 expression alone.

  8. biorxiv.org50

    Malignant and stromal partial EMT programmes and cetuximab outcome in head and neck cancer

    Standard bulk partial EMT (pEMT) scores in head and neck squamous cell carcinoma mainly measure stroma: across three single-cell datasets, the malignant arm (laminin-332 and hemidesmosome genes) sat in malignant cells while the stromal arm (fibrillar collagens, vimentin) sat in fibroblasts. A classifier and 12-gene core recovering the malignant arm predicted long progression-free survival in 40 patients given platinum and cetuximab (AUC 0.78 and 0.82), but the malignant arm tracked the Basal subtype, whose score performed as well or better (0.93) and also in two xenograft panels.

    Why it matters: It shows bulk pEMT scores reflect stroma rather than tumour cells and that the Basal subtype score captures cetuximab outcome.

CBACBA Frontier Insights (CFI)Chinese Biopharmaceutical Association (CBA)www.cba-usa.org