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Oct 2Fri
  1. biorxiv.org53

    P4HA1 sustains endocrine resistance in luminal breast cancer via regulation of cellular stress

    P4HA1, the alpha subunit of prolyl 4-hydroxylase, is upregulated in endocrine therapy-resistant luminal breast cancer cells, and its elevated expression correlates with shortened relapse-free survival in luminal breast cancer patients. Knockdown or pharmacologic inhibition of P4HA1 restored sensitivity to hormone therapy in resistant cells. The effect is mediated by ROS accumulation and endoplasmic reticulum stress, which also rises when P4HA1 inactivation is combined with endocrine treatment.

  2. biorxiv.org48

    Applying AlphaGenome Variant Impact for SNV Prioritization

    Empirical thresholds linking the AlphaGenome Variant Impact (AVI) quantile rank to clinical variant classifications are now established: a Youden-optimal cutoff of 0.9938 separates ClinVar pathogenic/likely pathogenic SNVs from benign ones, with broadly consistent cutoffs across molecular consequence classes and gene-disease groups. Applying the cutoff to 24,989 variants of uncertain significance flagged 11,357 (45.45%) with predicted functional effects comparable to pathogenic variants. In steroid-dependent asthma fine-mapping, AVI_QUANTILE showed little correspondence with SuSiE posterior inclusion probabilities, indicating AlphaGenome predictions capture information distinct from statistical fine-mapping.

  3. biorxiv.org45

    Genetic risk and inflammatory signaling converge on cell type-specific regulatory programs in type 1 diabetes

    A subset of type 1 diabetes-associated variants may drive beta-cell dysfunction by disrupting transcription factor binding at cell type-specific candidate cis-regulatory elements. The authors integrated epigenomic and single-cell multiomic data from human pancreatic islets with T1D GWAS variants, and used the deep learning model ChromBPNet plus TF footprinting to nominate several disease-associated SNPs predicted to alter chromatin accessibility at candidate TF binding sites. The work links noncoding variants to cell type-specific enhancer activity and provides candidates for future mechanistic studies.

  4. biorxiv.org59

    KRAS inhibition drives adaptive surfaceome remodeling and reveals ALPP/ALPPL2 as a targetable vulnerability in pancreatic cancer

    Quantitative temporal profiling of the global, phosphorylation, and surface proteome in PDAC shows that KRAS inhibition upregulates the cell surface protein ALPP through compensatory JAK2/STAT3 signaling. The authors developed a clinical-grade ALPP/ALPPL2-targeting antibody drug conjugate with site-specific MMAE conjugation, which showed single-agent efficacy in PDAC models and enhanced internalization and anti-tumor efficacy combined with KRAS inhibitors, pointing to a combination strategy to forestall KRASi resistance.

    Why it matters: It defines the KRASi-induced proteome and links a surface target to a clinical-grade ADC combination strategy against resistance.

  5. biorxiv.org53

    Phenotypes of ultra-rare variant carriers benchmark variant effect scores

    UKBBGym benchmarks coding and non-coding variant effect scores against plasma protein abundance and quantitative traits in ultra-rare variant carriers in the UK Biobank. Scores designed for coding and splicing variants outperform transcriptional-regulation scores on these phenotypes, and experimental assays do not consistently beat computational scores for missense effects. The benchmark is reproducible from public summary statistics for coding variants and avoids ascertainment bias of clinical labels.

    Why it matters: It supplies a population-phenotype benchmark for variant effect scores that avoids clinical-label ascertainment bias.

  6. biorxiv.org46

    A ncBAF to cBAF Switch Regulates Human Hematopoietic Progenitor Myeloid Differentiation

    Loss of the ncBAF subunit BRD9 in adult human hematopoietic stem and progenitor cells displaces ncBAF from chromatin and enhances cBAF recruitment to CEBPA target sites, skewing differentiation toward myeloid-derived suppressor cells that secrete elevated IL-8. Soluble factors from BRD9-deficient myeloid cells increased stemness of breast cancer cells in vitro. Bromodomain inhibition of BRD9, unlike degradation, minimally altered ncBAF binding and myeloid differentiation, showing BRD9 blocks MDSC differentiation independently of its bromodomain.

  7. biorxiv.org42

    Long-read PacBio HiFi sequencing resolves the genomic integration site and structure of the Nestin-CreERT2KEisc/J transgene

    PacBio HiFi whole-genome sequencing resolved the genomic integration site of the Tg(Nes-cre/ERT2)KEisc/J transgene, a widely used inducible CreERT2 line for neural stem and progenitor cell lineage tracing. The complete 13.7-kb transgene was reconstructed and mapped to chromosome 6 within intron 1 of Kcnd2, where insertion deleted 17.4 kb of endogenous DNA. Integration junctions enabled an allele-specific PCR assay for direct zygosity determination.

  8. biorxiv.org52

    KRASG12C Inhibition Remodels the Non-Small Cell Lung Cancer Surfaceome to Uncover Targetable Vulnerabilities

    KRAS G12C inhibitors remodel the cell surface proteome of KRAS G12C-mutant lung adenocarcinoma, and folate receptor alpha (FOLR1) emerges as a therapeutically actionable target that is significantly upregulated during treatment, part of an acute cellular state transition toward epithelial identity. Quantitative temporal proteomic profiling across cell lines, tumor models, and treatment durations identified this adaptation. Combining KRASi with mirvetuximab soravtansine-gynx, a clinically approved FOLR1-targeting antibody drug conjugate, enhanced tumor cell cytotoxicity and deepened response and tumor control in cellular and in vivo models.

  9. biorxiv.org40

    Acute Metabolic Switch by High-Dose Dehydroascorbic Acid: Rapid TCA Cycle Depletion and Early Signature of Methionine Trap within 1 Hour in KRAS-Mutant Cells

    High-dose dehydroascorbic acid triggers an abrupt metabolic switch rather than a linear buildup of oxidative stress in KRAS-mutant cells during 1-hour exposure. At 10 mM DHA, TCA cycle intermediates α-ketoglutarate and malate were rapidly depleted (Log2 FC < –2.0, p < 10–7), with glycerate and oxalate accumulation, plus free methionine buildup (Log2 FC = 1.14, p = 0.011) signaling an early methionine trap. At 1 mM DHA, only erythrulose accumulation (p = 0.030) and moderate glutamate consumption (p = 0.0086) occurred, with TCA homeostasis and viability preserved.

  10. biorxiv.org70

    The Genome In A Bottle HG002 assembly-based variant benchmark set enables comprehensive benchmarking of small and structural variants.

    The Genome in a Bottle Consortium's HG002 v5.0q benchmark set, built from a fully phased, highly curated diploid assembly, delivers confident small- and structural-variant calls in previously inaccessible regions such as segmental duplications, tandem repeats, homopolymers, and complex immune loci. Relative to v4.2.1 it adds 200 Mbp of callable sequence, increases variant detection by 18% for small variants and 3-fold for structural variants, and is available for GRCh37, GRCh38, and CHM13.

    Why it matters: It sets a new standard resource for validating sequencing technologies and variant callers in regions older benchmarks miss.

Oct 1Thu
  1. biorxiv.org55

    Sustained Ion Imbalances Enhance Ferroptosis

    Sustained imbalances in sodium, potassium and chloride ions drive ferroptosis across chemo-resistant cancer cell lines of different origins. Clinically approved modulators of CFTR and Kv7.2 inhibit ferroptosis independent of ion channel expression, and combining the ferroptosis inducer salinomycin with digoxin, a Na+/K+ ATPase inhibitor, enhanced ferroptotic cell death in vitro and reduced tumor growth in vivo beyond either agent alone. The work points to ion homeostasis as a broadly applicable ferroptosis target and to repurposing approved drugs for ferroptosis-associated diseases.

  2. biorxiv.org66

    Transcriptional rewiring of NF-κB by HBZ and Fra-2 drives inflammatory chemoresistance in Tax-negative adult T-cell leukemia/lymphoma

    HTLV-1 antisense protein HBZ stabilizes a Fra-2/p65 complex that rewires NF-κB transcription toward IL-1β in tax-negative adult T-cell leukemia/lymphoma, driving inflammatory chemoresistance. IL-1β was elevated in ATL patient sera and cells independently of proviral load, and blocking IL-1 signaling with anakinra or anti-IL-1β antibodies restored doxorubicin sensitivity in primary ATL cells. The work identifies the Fra-2-NF-κB-IL-1β axis as a targetable driver of chemoresistance.

    Why it matters: It identifies a druggable IL-1 signaling axis behind chemoresistance in tax-negative ATL.

  3. biorxiv.org64

    Early dynamics of a neutrophil interferon program drive immunotherapy resistance and limit durable anti-tumor immunity

    An interferon-stimulated gene program in neutrophils, detectable before tumors diverge in their response, predicts resistance to anti-PD1 therapy in preclinical triple-negative breast cancer models. Persistent neutrophil IFN signaling in blood and tumor tracked with treatment failure, while genetic disruption of type I or type II interferon signaling in neutrophils improved anti-PD1 efficacy and durable anti-tumor immune memory. The work positions IFN-responsive neutrophils as blood-based biomarkers and therapeutic targets.

    Why it matters: Identifies an early, blood-accessible neutrophil IFN signature that predicts anti-PD1 resistance and can be targeted.

  4. biorxiv.org41

    The Smac mimetic drug Xevinapant sensitizes triple negative breast cancer to radiotherapy-induced cell death in a TNFα dependent manner

    The Smac mimetic Xevinapant (AT406) sensitized triple-negative breast cancer cell lines to radiotherapy-induced cell death in vitro, with clonogenic assays in MDA-MB-231 cells showing a dose-enhancing factor of 1.57. Radiosensitization was significantly enhanced by TNF and mediated by TNF-dependent apoptosis, assessed by western blotting, flow cytometry and cell cycle analysis. The findings support combining radiotherapy with Xevinapant to improve local control in TNBC.

  5. biorxiv.org40

    Rapid whole genome- and annotation-based multilocus sequence typing of the fungal pathogen Histoplasma capsulatum

    Genome-based MLST schemes for Histoplasma capsulatum were built from 406 genome assemblies generated from public Illumina short-read samples, each with BUSCO completeness above 98%. Schemes derived from whole genome sequences and two annotation sources yielded over 8,000 markers and reproducibly separated all 7 lineages and 6 Suramericanum sublineages, with r2 values of 0.8-1.0 between schemes. The schemes run without high-performance computing, putting high-resolution typing within reach of ordinary laboratories.

  6. biorxiv.org44

    Phylodynamic analysis reveals asymmetric and accelerating global spread of dengue virus

    Urban dengue virus diversity originated in Asia in the first half of the 20th century, and Asia remains the main global source, seeding transmission in Africa and the Americas, according to phylogeographic analysis of global DENV genomes dating from the 1940s. Spread is asymmetric: lineages enter North America mostly from South Asia via a Northern Hemisphere seasonal-synchrony link, and rarely return to Asia. Travel volume, not climate, drives long-term spread, and the rate of spread to the Americas is increasing alongside a substantial rise in global travel from about 2010.

  7. medrxiv.org46

    Axitinib in Progressive Metastatic Pheochromocytoma and Paraganglioma: Results of a Phase II Study

    Single-agent axitinib produced confirmed partial responses in 35.3% of 17 treated patients with progressive metastatic or unresectable pheochromocytoma and paraganglioma, with median progression-free survival of 7.9 months and median overall survival of 29 months. Hypertension occurred in 79% of patients but was managed with antihypertensive therapy and dose modification, and no patient stopped treatment for toxicity. The phase II trial's efficacy compares favorably with sunitinib in this rare disease.

    Why it matters: First prospective single-arm data on selective VEGFR inhibition with axitinib in a rare cancer with few systemic options.

  8. biorxiv.org58

    Tumor suppressor-like mutations mark a dosage-constrained dependency in leukemia

    Recurrent heterozygous loss-of-function mutations in the transcription factor EBF3, a classic tumor suppressor signature, actually mark a gene essential for acute promyelocytic leukemia survival. PML::RARA drives EBF3 expression through a p300-dependent intronic enhancer, but excess EBF3 suppresses proliferation, so patient mutations calibrate EBF3 within a fitness corridor. p300 inhibition pushes EBF3 below the viability threshold, exploiting this dependency. The finding shows oncogenes can impose dosage constraints that produce mutations misread as tumor suppressor loss.

Sep 30Wed
  1. biorxiv.org70

    RNA splicing factor mutations drive myeloid neoplasm oncogenesis through protein complex poisoning

    Splicing factor mutations in myeloid neoplasms poison entire functional protein complexes, not just individual transcripts. Single-cell transcriptomics (10X-ONT, n = 21) and immunophenotype-resolved pauciproteomics (n = 78) across 62 patients and 20 healthy donors show that mutation-specific RNA mis-splicing decouples protein from transcript dynamics during hematopoietic differentiation, effects invisible to transcriptomics alone and validated in iPSC differentiation models.

    Why it matters: Protein-level consequences of splicing factor mutations are invisible to transcriptomics, changing how these oncogenic events should be studied.

  2. biorxiv.org56

    Endothelial AMBRA1 loss contributes to vascular dysregulation facilitating metastatic progression in early-stage melanoma

    Endothelial AMBRA1 loss drives vascular dysfunction and metastatic progression in early-stage melanoma. Melanoma-conditioned media or TGFβ1-3 ligands induced post-transcriptional AMBRA1 loss in endothelial cells, increasing proliferation, accelerating tubulogenesis, stabilizing Slug and Snail, and reducing Claudin-5, VE-cadherin and N-cadherin. In 121 non-ulcerated AJCC stage I/II melanomas classified AMBLor at-risk, loss of AMBRA1 in intratumoural and peritumoural blood and lymphatic vessels correlated significantly with metastatic progression.

  3. biorxiv.org51

    Dual inhibition of p38α MAPK and Casein kinase δ/ϵ as a novel treatment strategy for AR-independent and taxane-resistant advanced prostate cancer

    TAK-715, a dual inhibitor of p38 MAPK and Casein kinase δ/ε, showed efficacy against metastatic castration-resistant prostate cancer (mCRPC), including taxane-resistant lines and a highly aggressive metastatic variant, as a single agent and combined with taxanes. Its apoptotic effects occur via a mitochondrial-mediated pathway, and pathway analysis of bulk tumor RNA sequencing pointed to mitochondrial dysfunction and cell cycle arrest as top networks, with HES1 the top differentially expressed gene. Single-cell transcriptomics showed TAK-715 erodes subclonal populations driving cancer stemness, metastasis, and drug resistance, with findings validated in silico across multiple patient datasets.

  4. biorxiv.org54

    Novel Replication Stress-Associated High-Grade Serous Ovarian Cancer Models Recapitulate Diverse Tumour Ecosystems and Enable Preclinical Studies

    Syngeneic high-grade serous ovarian cancer models carrying distinct replication stress-associated alterations (Ccne1, Brd4, Myc, Ndrg1, Pik3ca overexpression and Brca1 heterozygosity) produced markedly different tumour fitness and ecosystem states on a common genetic background. BRCA1 heterozygosity linked to mesenchymal features, stromal expansion and immune exclusion, while Ccne1/Brd4 co-expression gave the highest replication stress with elevated CD47, confirmed in human HGSC specimens with high CCNE1 and BRD4. ATR and CD47 were then targeted therapeutically in intraperitoneal Ccne1/Brd4 models.

  5. biorxiv.org60

    Gene flux shapes diversity and evolution of the ancient 17q21.31 inversion polymorphism

    The common 979-kb 17q21.31 inversion in humans, long treated as a recombination-suppressing block, in fact permits ongoing gene flux between H1 and H2 haplotypes. Single-cell sperm sequencing showed near-complete suppression of single crossovers, but two-switch events of 17-150 kb occurred throughout the inversion at rates above genome-wide estimates, and 99 H1-H2 recombinant haplotypes were found in All of Us genomes. Recombinant haplotypes showed H2 additively increases female crossover rates across chromosomes, an effect not explained by KANSL1 duplications, and gene flux dates to roughly 100-500 thousand years ago.

  6. medrxiv.org51

    Somatic and Germline Telomere Biology in Sarcoma: Telomere Maintenance Is Acquired at Liposarcoma Dedifferentiation, and Genetically Longer Telomeres Are Associated With Liposarcoma Risk

    Telomere maintenance in sarcoma is histology-specific, with telomerase activation and ATRX/DAXX loss mutually exclusive across 11,792 patients in AACR Project GENIE. Dedifferentiated liposarcoma acquired telomere maintenance at dedifferentiation (28.0% vs 8.7% in well-differentiated liposarcoma), mainly through focal TERT amplification, and such alterations predicted shorter overall survival (HR 2.04). Mendelian randomization in FinnGen linked genetically longer telomeres to liposarcoma risk (OR per SD 4.10).

  7. medrxiv.org72

    CD3-engaging bispecific antibodies convert human regulatory T cells into cytotoxic effectors

    CD3-engaging bispecific T cell engagers convert human FOXP3+ regulatory T cells into an AP-1-imprinted hybrid cytotoxic state that contributes to tumor clearance. In newly diagnosed multiple myeloma patients treated with BTCE-based induction in the phase 2 GMMG-HD10/DSMM-XX/MajesTEC-5 trial, single-cell sequencing showed Tregs expressing GZMA, GNLY and NKG7, and in vitro BTCE-exposed Tregs killed tumor cells in a target- and dose-dependent manner. IMiDs amplified and reshaped this cytotoxic program, supporting BTCE-IMiD combination regimens.

    Why it matters: Reframes Tregs as active cytotoxic effectors of bispecific antibody therapy and gives a mechanistic basis for BTCE-IMiD combinations.

  8. biorxiv.org57

    Disease relevance and replicability of deep learning gene expression prediction

    Deep learning models that predict gene expression from DNA sequence owe their high overall correlation mostly to capturing whether genes are on or off, not to disease-relevant changes in expression among active genes; performance rises with how bimodal a gene's expression distribution is. The authors also found inconsistencies between published code and reported performance, and conclude that personalized genomic prediction in disease remains far from solved.

    Why it matters: Reported performance of popular gene-expression prediction models overstates their usefulness for disease research.

  9. medrxiv.org42

    Mapping tumor heterogeneity: ex-vivo drug responses in matched primary and metastatic tumors using a 3D functional precision platform

    Ex vivo 3D microtumor functional profiling showed that drug responses are largely preserved between primary tumors and their locoregional metastases, with concordance correlation coefficients of 0.93 to 0.97 across 275 drug responses. Split samples from the same tumor correlated at ρc=0.95, confirming assay reproducibility. Divergence grew with metastatic route, falling to 0.69 for colon-to-lung and 0.58 for ovarian-to-soft tissue/colon, suggesting single-site profiling is most informative for detecting resistance in distant hematogenic spread.

  10. biorxiv.org66

    Tissue resident CD4+ memory T-cells mark response to immune checkpoint inhibition in high-grade glioma

    Tissue-resident CD4+ memory T cells mark which high-grade gliomas respond to combined PD-1 and CTLA-4 inhibition. In a syngeneic hypermutated glioma model, response involved clonal expansion of tumor-reactive cytotoxic T cells and infiltration of CXCR6+ CD4+ Trm cells, with CD4 stem-like memory cells showing interferon responses rather than exhaustion. In IDH1 wildtype glioblastoma patients treated with neoadjuvant pembrolizumab, CD4+ Trm association with prolonged overall survival was confirmed.

    Why it matters: Identifies a T-cell subset that predicts checkpoint inhibitor response and survival in glioblastoma.

  11. biorxiv.org40

    Identifying, phasing, and structurally annotating sex chromosomes for genome assemblies using CBS-tools

    CBS-tools is a k-mer based pipeline using whole-genome sequencing of a few sex-identified isolates to identify sex chromosomes in genome assemblies. It predicted the correct heterogametic sex in all 31 species tested from public datasets, verified and corrected phasing of sex chromosomes between haplotypes, and delimited the sex-determination region boundary via an interactive web platform. It works for both unexplored and well-examined sex chromosome systems.

    Why it matters: Validated method that automates sex chromosome identification, phasing and SDR annotation across 31 species.

  12. biorxiv.org50

    Evolutionary dynamics of the insertion sequence IS6110 in the Mycobacterium tuberculosis complex

    Analysis of 10,000 Mycobacterium tuberculosis complex genomes, using a reference-free tool and ancestral state reconstruction, maps the evolutionary dynamics of insertion sequence IS6110. Copy numbers range from 1 in some clades to more than 30 in La3 (M. orygis), birth rates scale linearly with copy number, and the 5% most frequently targeted regions account for half of all independent insertion events. The authors propose a niche constraints model in which insertions accumulate where DNA properties suit the element and functional cost to the host is low.

    Why it matters: First genome-wide view of IS6110 dynamics across 10,000 MTBC strains, with a reference-free insertion-calling tool.

  13. biorxiv.org69

    Functional Deorphanization of Tumor-reactive TCRs Uncovers a Landscape of Shared, Immune Dominant Antigens across Cancers

    The TWISTAR platform deorphanizes single-cell-derived TCRs against tumor transcriptomes and directly validates TCR engagement, so it recovers only functionally immunogenic antigens. Applied to melanoma, breast, and hepatocellular carcinoma patients responding to immune checkpoint blockade, it shows tumor-reactive TCRs recognize many targets beyond neoantigens, including peptides from unannotated coding sequences and novel transcripts. Many antigens are shared across patients and cancer types, with multiple T cell clones converging on a few immune dominant epitopes, supporting pan-cancer vaccine development.

    Why it matters: Identifies shared, immune dominant tumor antigens beyond neoantigens, opening targets for pan-cancer vaccines.

Sep 29Tue
  1. biorxiv.org61

    Genomic correlates of metastatic competence and progression in human melanoma

    Metastatic competence in primary cutaneous melanoma is marked by somatic copy-number alterations and chromosomal instability rather than oncogenic point mutations, which were largely shared between primaries and metastases. Sequencing of 247 stage I/II primary melanomas and 60 matched metastases with median followup of 92 months yielded OncoCycle, a six-gene copy-number signature that predicted relapse independently of clinicopathological features. Matched pairs showed progression driven by continued copy-number evolution, with both monoclonal and polyclonal seeding resolved by clonal reconstruction.

    Why it matters: A six-gene copy-number signature predicts melanoma relapse and reframes metastasis as copy-number driven.

  2. biorxiv.org60

    BRCA2 loss drives a PKM1-dominant glycolytic state that is selectively lethal to pyruvate kinase activation

    BRCA1/2 loss is linked to a PKM1-dominant glycolytic state with elevated pyruvate kinase activity, found across 10,619 TCGA tumors and isogenic BRCA1/2-deficient models. PKM activation with small-molecule activators, including the FDA-approved mitapivat, triggered superoxide accumulation, disrupted PINK1-dependent mitochondrial quality control, induced DNA damage, and selectively killed BRCA2-deficient tumors in vivo while sparing BRCA2-proficient counterparts. The work recasts homologous recombination deficiency as a metabolic state and identifies PKM activation as a candidate therapy for HR-deficient cancers.

    Why it matters: It turns HRD into a druggable metabolic vulnerability with an already FDA-approved activator.

  3. biorxiv.org53

    SMYD3 protein degraders in HPV-negative head and neck squamous cell carcinoma.

    SMYD3 PROTACs, unlike catalytic inhibitors that lack phenotypic efficacy, degrade SMYD3 and curb proliferation and invasion in HPV-negative HNSCC cell lines. The compound IAP-08 degrades SMYD3 with a DC50 of about 177 nM and Dmax of about 90%, forms ternary complexes with XIAP E3 ligase, and shows favorable pharmacokinetics in vivo. Degradation, but not enzymatic inhibition, reprograms cell cycle, EMT and type I IFN response genes, supporting clinical development of IAP-08 in a disease where SMYD3 is overexpressed in about 60% of tumors.

    Why it matters: It reframes SMYD3 as undruggable by inhibitors alone and provides a degrader with in vivo feasibility for HPV-negative HNSCC.

  4. biorxiv.org63

    SON-mediated circular RNA suppression promotes PKR signaling and radiation resistance in glioblastoma

    The splicing co-factor SON suppresses circular RNA biogenesis in glioblastoma, and its elevation in radiation-resistant GBM is linked to widespread circRNA loss. SON knockdown raised circRNA abundance and attenuated PKR/NFκB signaling, and overexpression of the SON-suppressed circUSP1 and circSUCO reduced PKR activation and selectively decreased clonogenic survival after irradiation in radiation-resistant cells, with little effect on parental cells. The work defines a SON/circRNA/PKR pathway and points to PKR-inhibitory circRNAs as tools to resensitize resistant GBM to radiotherapy.

    Why it matters: It identifies a specific SON/circRNA/PKR pathway behind acquired radiation resistance in glioblastoma.

  5. biorxiv.org58

    Epigenetic progression of pancreatic cancer to aggressive subtypes involves alternate routes of lineage reprogramming in subtype-intermediate progenitor cells

    Single-cell ATAC-seq of 33 primary tumors and 7 metastases from 39 PDAC patients, paired with 10 single-cell RNA-seq profiles, maps the cis-regulatory landscape underlying malignant cell state plasticity. GATA6+/KRT17+ co-accessibility marks a classical-basal subtype-intermediate progenitor state (SIP) with limited epigenetic reprogramming and better clinical outcomes. Classical tumors repressing basal accessibility activate neural-like progenitor and tuft lineage enhancers, while basal committed tumors show esophageal transdifferentiation, both with poorer outcomes and distinct immune and stromal phenotypes.

    Why it matters: Defines epigenetic lineage routes and a progenitor state that stratify PDAC outcomes and tumor microenvironment phenotypes.

  6. biorxiv.org57

    Early-life colonization by enterotoxigenic Bacteroides fragilis remodels gut epithelial stem cell states to drive colorectal cancer susceptibility

    Early-life colonization by enterotoxigenic Bacteroides fragilis (ETBF) remodels colonic epithelial stem cell states and drives colorectal cancer susceptibility. Neonatal ETBF exposure expanded Lgr5+ stem cells, enhanced Atoh1+ secretory differentiation, induced distal colon-specific Wnt hyperactivation, and increased precancerous lesions in ApcMin/+ mice. Non-toxigenic B. fragilis colonization in the same window prevented lesion formation, showing developmental context determines protection or predisposition.

    Why it matters: Defines a developmental window in which microbial toxin exposure imprints colorectal cancer risk in mice.

  7. biorxiv.org55

    Combining interstrand crosslinking agents with histone deacetylase inhibitors against high grade IDH mutant gliomas

    The interstrand crosslinking agent KL-50 retains antiproliferative activity against MMR-deficient IDHmut glioma models, where temozolomide GI values rose 2.2- to 30.4-fold, and extends median survival in BT142 orthotopic xenografts from 107.5 to 194 days. KL-50 plus the HDAC inhibitor belinostat shows synergistic cytotoxicity in BT142, 905, and TS603 cultures, with CRISPR screening implicating PKMYT1 as a determinant of sensitivity. The work offers a preclinical route past MMR-associated TMZ resistance.

    Why it matters: Provides a preclinical option for IDHmut gliomas with MMR-associated temozolomide resistance.

Sep 28Mon
  1. medrxiv.org40

    A serum thyroid hormone metabolite test for molecular diagnostic evaluation of thyroid nodules

    A blood test measuring serum thyroid hormone metabolites by liquid chromatography tandem mass spectrometry distinguished differentiated thyroid cancer from benign thyroid nodules, validated prospectively in cohorts of 392 and 399 subjects. Combined validation showed 99.7% specificity and 92.1% sensitivity; in indeterminate Bethesda III-IV nodules, specificity was 100.0% and sensitivity 93.5%. The model offers a preoperative molecular option for nodules that cytology leaves unclear.

  2. biorxiv.org54

    Transcriptional networks underlying tumour plasticity in small-cell lung cancer

    Single-cell multi-omics of small-cell lung cancer resolved distinct cell states along the neuroendocrine-to-nonneuroendocrine axis, including a previously unrecognised Intermediate state of low-identity immunogenic cells that serves as an obligatory route in lineage transition. A Boolean Bayes model of transcription factor networks (BoBa-T) predicted state regulators, and RORB was validated as a gatekeeper of the neuroendocrine state: its inactivation pushes NE cells into the Intermediate state, upregulates immunogenic programs, and inhibits tumour growth in immunocompetent hosts.

    Why it matters: Identifies an obligatory immunogenic intermediate state and RORB as a druggable gatekeeper of SCLC lineage plasticity.

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