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#预印本

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Oct 7Wed
  1. biorxiv.org53

    A map of RBP-miRNA regulatory connections for deciphering the mechanisms of transcriptome remodeling in cancer

    A pan-cancer analysis maps regulatory connections between 34 RNA-binding proteins and 28 miRNAs, drawing on RNA-seq from RBP inhibition experiments, cell lines and tissues, plus thousands of tumor and control samples across 17 human cancers. RBP-driven regulation of miRNA activity proved common in tumors and shaped heterogeneity in miRNA activity profiles. DDX55 emerged as a pan-cancer negative regulator of the tumor-suppressor miR-29-3p family; inhibiting DDX55 restored miR-29-3p gene-silencing activity and reduced cancer cell viability.

  2. biorxiv.org56

    SLC25A28 is a synthetic lethal vulnerability in nucleotide excision repair-deficient cancers

    SLC25A28 is a synthetic lethal vulnerability in nucleotide excision repair (NER)-deficient cancers. A genome-wide CRISPR-Cas9 screen in an ERCC4-null RT112/84 bladder cancer cell line nominated SLC25A28 as the top candidate, and clonogenic assays confirmed selective viability loss in cells deficient for ERCC2, ERCC3, ERCC4, or ERCC5, with inducible knockout suppressing ERCC4-deficient xenograft growth in vivo. Loss of SLC25A28 raised intracellular ROS and DNA damage signatures, pointing to mitochondrial iron homeostasis as a platinum-free target in the roughly 10% of bladder, upper urinary tract, and endometrial cancers with deleterious NER alterations.

  3. biorxiv.org48

    Extracellular vesicle cross-linking coupled with solid-phase purification facilitates discovery of ribonucleoprotein complexes assembled on EV RNAs.

    EV-CLASP and EV(r)-CLASP are two chemical biology platforms for profiling ribonucleoprotein complexes on extracellular vesicle RNAs. EV-CLASP maps the native RNP landscape packaged inside EVs, while EV(r)-CLASP identifies host proteins that associate with EV-derived RNAs after uptake by recipient cells. Both use 4-thiouridine metabolic labeling, 365 nm UV crosslinking, solid-phase reversible bead purification, and quantitative mass spectrometry.

  4. biorxiv.org47

    p38α MAPK integrates opposing oncogenic APC/β-catenin/TCF and GUCY2C tumor-suppressor axes in colorectal cancer

    p38α MAPK is the intermediary through which oncogenic APC/β-catenin/TCF signaling silences the GUCY2C tumor-suppressor axis in colorectal cancer. In four conditional human CRC cell lines and human colon organoids, APC/β-catenin/TCF signaling suppressed p38α phosphorylation and activity, while inhibiting that pathway restored p38α signaling and enriched phosphorylated p38α at the GUCA2A promoter. RNA sequencing showed p38α controls a substantial subset of APC/β-catenin/TCF-regulated genes in CRC cells and patient tumors, and CPTAC analysis found reduced phosphorylation of p38α and its upstream kinases MKK3 and MKK4 in human CRC.

  5. biorxiv.org60

    MERFISH-based pooled genetic screening reveals cell non-autonomous phenotypes in intact tissue

    An amplification-free MERFISH pooled screening method reads perturbation barcodes and endogenous RNAs directly, boosting barcode recovery ~10-fold and transcripts 2.5-fold over an enzymatic-amplification workflow. Applied to a mosaic mouse liver screen targeting ~200 hepatocyte genes across 1.5 million cells, it mapped cell-autonomous and neighbor effects, including pDC-like cell accumulation near V-ATPase-impaired hepatocytes and angiogenic responses near Vhl-perturbed hypoxic hepatocytes.

Oct 6Tue
  1. biorxiv.org56

    Binding kinetics enable tumor-selective MAPK and growth suppression by a Type 1 RAF Inhibitor

    The Type 1 RAF inhibitor ELV-3111 exploits fast binding dissociation to drive paradoxical MAPK hyperactivation in normal tissues while sparing RAS-mutant tumors, where RAF is already primed. This yields selective MAPK and growth suppression in RAF-dimer-driven models. Combined with a MEK inhibitor, it produced durable regressions in RAS-mutant and BRAF-mutant models, including one refractory to current therapies, with favorable tolerability.

  2. biorxiv.org53

    Genomic classification and immune profiling define mucosal melanoma

    Genomic sequencing of 339 patients with mucosal melanoma identified four mutually exclusive genomic subtypes, CDK4/MDM2/CCND1, SF3B1-mutated, TP53/ATRX, and Triple WT, tied to distinct anatomic sites but similar outcomes. Compared with cutaneous melanoma, mucosal tumors showed less T cell infiltration and more CD163+ tumor-associated macrophages, which increased with progression and immunotherapy resistance and engaged non-regulatory T cells through GAL9-TIM-3 interactions, nominating TIM-3 blockade as a therapeutic strategy.

  3. biorxiv.org50

    A long-term organotypic slice culture model of patient high-grade glioma preserving tumor heterogeneity and architecture, and specificity of CAR T cell targeting

    A patient-derived high-grade glioma organotypic slice culture (GOSC) platform preserved tumor histopathology, cell heterogeneity, microenvironment and architecture for at least 28 days in culture. Slices were grown under in situ-like conditions of 4% oxygen, 2.5 mM glucose and no added growth factors. GOSCs retained parental immunotherapy target expression, and CAR T cells showed target-specific killing in co-culture, supporting extended preclinical testing of therapeutics.

  4. biorxiv.org57

    A microbiota-dependent gut bile acid axis links germline mutant p53 to distal tumour growth.

    Germline mutant p53 reshapes the intestinal environment before tumours form: tumour-naive Trp53R172H/+ mice showed increased intestinal permeability, colonic inflammation with elevated NF-kappaB signalling, and altered bile acid metabolism, including higher levels of the microbiota-derived secondary bile acid deoxycholic acid (DCA), which correlated most strongly with distal tumour burden. Microbiota depletion reduced distal tumour growth and normalized the bile acid and inflammatory changes, while faecal filtrate transfer from mutant donors to wild-type recipients induced colonic inflammation and enhanced distal tumour growth. The work identifies a mutant p53-gut axis relevant to cancer predisposition in Li-Fraumeni Syndrome.

  5. biorxiv.org51

    A near-ubiquitous plasmid characterises Second Pandemic Yersinia pestis

    A cryptic 34 kb plasmid, pTP33, is present in almost all Second Pandemic Yersinia pestis strains and undetectable in all other ancient strains, revealed by variation-graph pan-genomics of 110 new and 12 published ancient plague genomes. pTP33 is a phage-plasmid-like element with homologues in insect-associated Enterobacterales, suggesting it widened vector range beyond the rat/flea cycle and helps explain the Second Pandemic's far higher mortality, up to 60% of Europe's population in the Black Death, versus the Third Pandemic.

  6. biorxiv.org55

    KRAS-driven metabolic reprogramming of enhanced MFSD2A-mediated lysophosphatidylcholine scavenging promotes survival and progression of pancreatic ductal adenocarcinoma

    Oncogenic KRAS upregulates MFSD2A, driving PDAC cells to scavenge extracellular unsaturated lysophosphatidylcholines and sustain AKT-mediated survival. Plasma lipidomics across 93 newly-diagnosed resectable PDAC cases, 43 chronic pancreatitis patients, and 93 matched controls showed pronounced reductions in circulating LysoPCs associated with PDAC. Blocking MFSD2A or restricting LysoPCs suppressed AKT signaling, increased apoptosis, and slowed tumor growth, and repurposing edelfosine against this axis produced anti-cancer effects in vitro.

  7. biorxiv.org42

    EPHA4 Regulates the Transition between Mesenchymal and Hybrid States in TNBC

    EPHA4 regulates the shift between mesenchymal and hybrid epithelial/mesenchymal states in triple-negative breast cancer. EPHA4 is enriched in mesenchymal TNBC cells, and its knockout in MDA-MB-231 xenograft and 4T1 syngeneic models drives cells toward hybrid E/M phenotypes, reducing invasion while enhancing metastatic colonization. Clinically, EPHA4 expression is lower in secondary metastases than in primary tumors, complicating therapeutic targeting of this pathway.

  8. biorxiv.org50

    Radiotherapy-induced vascular dysfunction alters neutrophil phenotype to promote tumor cell colonization of mammary adipose tissue

    Neutrophils drive circulating tumor cell colonization of irradiated mammary tissue in lymphocyte-deficient mice, a process that systemic neutrophil depletion abates. Neutrophils persist in the mammary tissue up to 10 days post-radiotherapy, acquire a PMN-MDSC-like phenotype induced by the RT-damaged microenvironment, and form an NF-kB-dependent positive feedback loop with irradiated endothelial cells that increases barrier permeability and vascular remodeling. The work identifies neutrophil-vascular crosstalk as a candidate target for preventing recurrence after radiotherapy in triple-negative breast cancer.

  9. biorxiv.org54

    RNA and protein are not interchangeable in single-cell spatial multi-omics

    Paired Xenium profiling of 21 matched RNA and protein targets across roughly 1.8 million cells from lung adenocarcinoma and metastatic castration-resistant prostate cancer shows the two modalities are not interchangeable. Lineage markers were concordant, but PD-1, PD-L1 and LAG-3 showed little agreement, and spatial organization was more discordant than overall abundance. The work sets rules for when spatial transcriptomics can proxy for protein and when orthogonal validation is needed.

  10. biorxiv.org52

    HMGA2 Expression in Pancreatic Ductal Adenocarcinoma Controls Tumor Microenvironment and Immunosuppression via IL1α

    HMGA2 expression marks basal-like pancreatic ductal adenocarcinoma cells and shapes an immunosuppressive tumor microenvironment. HMGA2 binds the IL1α promoter in tumor cells, raising IL1α levels, which polarizes fibroblasts toward immunosuppressive CAFs with IL6 and LRRC15 upregulation, increases regulatory T cells and reduces CD8+ T cells. Blocking IL1α signaling disrupts this phenotype and improves tumor control when combined with KRAS inhibitors.

  11. biorxiv.org47

    Conservation of gene co-expression networks and neuropsychiatric-neurological disease gene programs between mouse and human frontal cortex at single-cell resolution

    Co-expression partners of individual genes are only modestly conserved between mouse medial PFC and human dorsolateral PFC: across 13,214 genes and 246,211 single-nucleus RNA-seq profiles, the median partner similarity was 0.169, rising to at most 0.349 after noise correction. Co-expression modules, however, were strongly preserved, and four of five human modules recurred in an independent human dataset. Neuropsychiatric disease genes were no more conserved than matched control genes, and no disease gene showed different partners across species, temperating assumptions of gene-level conservation in mouse models.

  12. biorxiv.org51

    Discovering Latent Scientific Concepts through Discrete Representation Learning

    Kodiak, a discrete representation learning architecture, learns latent scientific concepts from small, curated scientific imaging datasets through Sinkhorn-balanced codebook assignments, avoiding the instability of continuous self-supervised adaptation where teacher representations drift. Across five scientific imaging domains, including multiplex immunofluorescence for pancreatic cancer pathology and scanning electron microscopy, it improves representation quality under both foundation-model adaptation and training from scratch. The learned concepts are interpretable, reusable, and produce spatially coherent concept maps supporting cell phenotyping, spatial niche discovery, tissue organization, and materials characterization.

  13. biorxiv.org58

    Genetic dissection of DNA damage response pathways reveals divergent modulation of PD-1 blockade response in colorectal cancer

    A systematic in vivo screen of altered DNA damage response genes in a genome-edited murine model of MSS colorectal cancer shows that DDR defects have pathway-specific effects on PD-1 blockade response. Loss of Brca1, Brca2, Atm and Fanca enhanced anti-PD-1 response, while Atr and Msh6 deficiency predicted poor benefit, and BRCA1 alterations tracked with improved survival in patients from the MSK-IMPACT cohort. Pre-treatment with pharmacologic ATM inhibition enhanced the antitumor activity of PD-1 blockade in MSS colorectal cancer.

  14. biorxiv.org50

    RBFOX2 restrains oncogenic cell plasticity in Group 3 medulloblastoma

    The splicing regulator RBFOX2 suppresses oncogenic cell plasticity in Group 3 medulloblastoma. OTX2 antagonizes RBFOX2 by shifting its RNA-binding landscape away from cytoskeletal loci, and RBFOX2 loss drives proliferative, mesenchymal-like and undifferentiated states with enhanced oncogenic properties. RBFOX2-low states mark highly plastic cell populations in patient tumors and xenografts.

  15. biorxiv.org49

    Hidden but Expanding Sampling Bias Distorts Prokaryotic Genome Collections

    Sampling bias in public prokaryotic genome collections is widespread, growing in recent years, and distorts gene frequency estimates and the representation of genomic diversity. A new method, PhyloThin, detects oversampling by comparing phylogenetic relationships to random-sampling expectations; applied to 402 prokaryotic species in the NCBI genome database, it finds the effective number of samples is 41% lower than the actual number. Accounting for oversampling reveals greater genomic diversity and more undiscovered genes than current data suggest, with implications for pathogen surveillance and discovery of novel genetic functions.

  16. medrxiv.org48

    Resection of highly functionally connected glioma regions predicts long-term cognitive preservation

    Resecting more glioma regions with high functional connectivity (HFC) on preoperative MEG predicted better long-term cognitive outcome rather than worse. In a preregistered analysis of 54 adults with diffuse glioma, resected HFC voxels were associated with less cognitive decline at ~1 year (48% declined; OR 0.85, P = .02) and showed no association with neurological decline at short-term (48% declined; OR 0.98) or long-term follow-up (27% declined; OR 0.99). The finding runs counter to the short-term risk attributed to HFC areas and supports non-invasive MEG connectivity mapping to guide the onco-functional balance in glioma surgery.

  17. biorxiv.org46

    Disease-associated mutations directionally modulate epigenetic age in iPSC-derived tissues

    Epigenetic age progressively increases with serial passaging of iPSC-derived lung organoids (alveolospheres), measured by multiple epigenetic clock models, providing a reproducible in-vitro way to re-establish aging trajectories lost at reprogramming. Disease-associated mutations added cell-intrinsic shifts in epigenetic age across multiple models, marking disease state as an independent modulator of epigenetic clocks. The work extends iPSC systems to modeling age-associated cellular states beyond genetics.

  18. biorxiv.org49

    Distinct sequence grammars of nucleosomal and linker DNA shape mutational and methylation landscapes in cancer

    DeepND, an interpretable deep learning framework, distinguishes nucleosomal from inter-nucleosomal DNA and identifies 210 sequence motifs of 2-16 bp length that are significantly enriched or depleted in nucleosomal DNA. Forty-four of these motifs show cancer-type-specific enrichment or depletion of somatic mutations, and six are associated with differential DNA methylation levels. In lung and endometrial cancers, mutations show a significant ~10-bp periodic enrichment pattern across distinct minor-groove orientations, linking mutational and repair processes to nucleosome rotational positioning.

  19. biorxiv.org47

    The mammalian genome is punctuated by regularly spaced nucleosome islands

    A deep-learning model trained on genome-wide nucleosome maps from mouse embryonic stem cells predicts nucleosome occupancy from primary DNA sequence alone and separates shared biological signal from assay-specific noise. In silico mutagenesis pinpointed positioning regions built from short 5-to-20-base-pair motifs in dense regulatory windows, with CCCTC-binding factor motifs in SINEs, zinc-finger-bound motifs in LINEs, and microsatellite repeats acting as potent organizers of nucleosome phasing. This extends sequence-encoded nucleosome architecture, known in yeast, to mammalian genomes.

  20. biorxiv.org50

    Matched primary-metastasis single-nucleus and spatial profiling of leiomyosarcoma identifies antigen-presenting fibroblasts at the tumor-organ interface

    Matched primary and metastatic leiomyosarcoma samples reveal organ-specific malignant programs, with a stress- and hypoxia-associated program in lung metastases and a proliferative, matrix-remodeling program in liver metastases. Antigen-presenting cancer-associated fibroblasts were enriched in metastases (p = 0.001) and formed a band at the tumor-organ interface, unlike their sparse random distribution in primaries. Spatial profiling of 21 patients further defined three histomolecular phenotypes, including a GPNMB phenotype potentially targetable by GPNMB-directed therapies.

  21. biorxiv.org40

    Spatial transcriptomics reveals tumour cell-intrinsic and microenvironmental features associated with survival in high-grade serous ovarian carcinoma

    Spatial transcriptomics of 122 treatment-naive high-grade serous ovarian carcinomas, using a 480-gene panel, identified 61 tumour-intrinsic genes nominally associated with overall survival, with five linked to longer and nine to shorter survival. 46 of these 61 associations were lost when expression was aggregated across all cells, showing that whole-tissue profiling obscures tumour-cell-specific survival signals. Multiple tumour-proximal immune populations predicted longer survival, while two fibroblast populations predicted shorter survival. The findings resolve the cellular origins of bulk survival signatures in HGSOC and link tumour-intrinsic expression to the surrounding microenvironment.

  22. biorxiv.org45

    KSHV upregulates the long non-coding RNA PURPL via p73 to suppress p53

    KSHV upregulates the oncogenic lncRNA PURPL through p73 rather than its usual driver p53. LANA stabilizes p73, which binds the PURPL promoter; p73 knockdown abrogates PURPL upregulation after KSHV infection. ASOs targeting PURPL reduced PEL cell proliferation and increased acetylated p53 levels, suggesting PURPL as a therapeutic target in KSHV-associated malignancies.

  23. biorxiv.org50

    Revisiting AXL as a therapeutic target in soft tissue sarcoma: dubermatinib and bemcentinib effects are largely independent of AXL inhibition

    The AXL inhibitors dubermatinib and bemcentinib reduce viability and induce apoptosis in HT-1080 and SK-LMS-1 soft tissue sarcoma cell models, but shRNA-mediated AXL knockdown fails to reproduce these antiproliferative effects or alter drug sensitivity. Transcriptomic changes induced by the drugs correlate weakly with AXL knockdown, and most drug-regulated genes are AXL-independent. Although STS shows high median AXL mRNA expression in TCGA data, AXL expression was not associated with patient survival, so the rationale for AXL-directed therapy may be reconsidered.

  24. biorxiv.org49

    Mechanistic Decoding of Pharmacodynamic Intratumoral Heterogeneity: A Pan-Cancer Regulatory Framework

    A pan-cancer analysis links single-cell transcriptomes from 1,279 samples across 24 cancer types with drug-response profiles for 1,218 compounds, defining 425 hub genes associated with predicted treatment-response heterogeneity. A multi-omics case study in lung adenocarcinoma identifies four regulatory classes of candidate associations, including 3 transcription factors, 41 genomic alterations, 5 ligand-receptor pairs and 8 splicing genes, converging on 6 core tumor-intrinsic pathways. An online platform enables state-resolved drug-response analysis and candidate-gene exploration.

  25. biorxiv.org53

    Metabolic rewiring induces a viral mimicry-mediated quiescence in glioblastoma

    Inducing the polyamine-catabolic enzyme SSAT1 with the polyamine analogue DENSpm triggers a reversible, chemoprotective growth arrest in patient-derived glioblastoma stem cells, independent of stemness, differentiation or senescence. The arrest coincides with reduced eIF5A hypusination, lower global protein translation, and a rise in double-stranded RNA that activates type I interferon signalling; knocking down the mitochondrial antiviral-signalling protein partially reverses it. Single-cell and cohort analyses show susceptibility to this quiescence is set by intrinsic inflammatory tone and lysosomal dependency.

  26. biorxiv.org47

    A Novel ACLY Inhibitor Induces Transcriptional and Metabolic Reprogramming to Overcome Tyrosine kinase inhibitor Resistance in Lymphoma

    The novel ACLY inhibitor VCB1 blocked recombinant human ACLY with an IC of 0.9 uM and suppressed growth of lymphoma cells, retaining potency in TKI-resistant models: 1.62 uM in lorlatinib-resistant SUPM2-LR1000 cells and 0.278 uM in BTK inhibitor-resistant mantle cell lymphoma cells, where the existing inhibitor BMS-303141 was far less active. Multi-omics profiling showed VCB1 suppressed de novo lipogenesis, activated the integrated stress response with induction of ATF4, DDIT3 and related genes, and disrupted nucleotide biosynthesis. The work identifies ACLY as an actionable vulnerability for overcoming TKI resistance in lymphoma.

  27. biorxiv.org47

    A Novel NO Donor 3A72 Activates Mitochondrial-Associated Endoplasmic Reticulum Membrane Structures to Induce Ferroptosis in Triple-Negative Breast Cancer

    The nitric oxide donor 3A72, a furan-coumarin-based compound, suppresses triple-negative breast cancer cell proliferation and restricts xenograft tumor growth, with efficacy matching paclitaxel but with enhanced safety and reduced systemic toxicity. Mechanistically, 3A72 releases NO to cause calcium overload, binds IP3R and ACSL4, and converges on mitochondria-associated ER membranes, where ROS generation couples with lipid remodeling to drive ferroptosis through malondialdehyde accumulation. The findings identify the MAMs calcium-lipid hub as a structural scaffold for antitumor drug development.

Oct 3Sat
  1. medrxiv.org42

    HPV-Stratified Causal Digital Twins for Personalized Survival Benefit Estimation in Head and Neck Cancer

    A causal digital-twin model trained on the RADCURE cohort (n = 3,346) estimates patient-specific 2-year survival benefit of chemoradiotherapy versus radiotherapy alone in head-and-neck cancer, stratified by HPV status. In HPV-negative disease it discriminated well (test AUC = 0.72; C-index = 0.81) and estimated a mean survival benefit of 0.13 for CRT, with greater benefit in node-positive, good-performance patients. Decision-curve analysis favored tau-guided selective CRT over uniform treatment policies; heterogeneity was attenuated in HPV-positive disease.

  2. medrxiv.org53

    Lanreotide for Advanced Pheochromocytoma and Paraganglioma: Results of a Multicenter Phase II Trial

    Lanreotide depot/autogel 120 mg every 4 weeks showed antiproliferative activity in 18 patients with advanced or metastatic pheochromocytomas and paragangliomas, most of them (78%) carrying SDHx mutations. Disease stabilization occurred in 11 of 13 patients (85%) at about 1 year, with two partial responses and a median tumor growth rate of 0.00124/day (doubling time 559 days), consistent with a median PFS of at least 2 years. Treatment was well tolerated, with no discontinuations due to toxicity. The findings support somatostatin analogues as an option for SSTR-positive PPGL before escalating to more aggressive treatments.

Oct 2Fri
  1. biorxiv.org62

    Topoisomerase-mediated resolution of negative DNA supercoiling sustains human transcription and gene activation

    Topoisomerase-mediated resolution of negative DNA supercoiling is required for productive transcription in human cells. Acute topoisomerase perturbation lets negative supercoiling accumulate around transcription start sites, slows RNAPII elongation, increases promoter-proximal pausing, and, upon TOP1 depletion, raises gene expression noise by cutting transcriptional burst size and frequency while weakening enhancer-promoter loops. During T-cell activation, impaired supercoiling resolution compromises rapid gene upregulation.

  2. biorxiv.org67

    Genome-wide mapping of endogenous topoisomerase cleavage complexes reveals TOP1 at the interface of DNA topological regulation and genome instability

    Protein-DNA adduct immunoprecipitation followed by sequencing (pDAIP-seq) detects endogenous topoisomerase cleavage complexes genome-wide without stabilization by topoisomerase poisons, revealing that camptothecin, required by prior TOP1cc profiling methods, substantially alters the genomic distribution of TOP1cc. Endogenous TOP1cc were reduced by transcriptional suppression and increased by TOP2A depletion, and their positioning was largely specified by local DNA sequence context. The method also maps TOP2cc, TOP3cc and SPO11-DNA intermediates in mouse testis and identifies endogenous TOP1cc as a potential major source of spontaneous DNA breaks in human cells.

    Why it matters: pDAIP-seq maps endogenous topoisomerase cleavage complexes genome-wide without poisons, changing how TOP1cc distributions are measured.

  3. biorxiv.org50

    Epithelial to mesenchymal transition and M2 macrophages drive aggressiveness in murine and human sarcomatoid urothelial carcinoma.

    A new murine model of sarcomatoid urothelial carcinoma, BBN966, closely mirrors the human disease: it lacks basal and luminal gene expression, shows the highest epithelial to mesenchymal transition upregulation, and has a higher proportion of M2 macrophage gene expression. In the largest PD-L1 IHC cohort to date, 20 of 38 (52.6%) human SUC had CPS > 50, and anti-PD1 significantly inhibited BBN966 tumor growth, supporting the model for testing new therapies.

  4. biorxiv.org58

    Spatially coordinated RTK-ERK signaling dynamics shape osteosarcoma single-cell drug response in the lung microenvironment

    MCL1 inhibition kills osteosarcoma lung metastasis cells ex vivo, but surviving ERK-high/Fra-1-high cells accumulate at the tumor-lung interface through FGFR-mediated ERK signaling amplified by neighboring tumor-cell lysis, marking an adaptive resistant state linked to Nrf2 and HMOX1 upregulation. Combining FGFR inhibitor fexagratinib or the broad-spectrum RTK inhibitor pazopanib with the MCL1 inhibitor suppressed this adaptive ERK activation and improved efficacy ex vivo and in vivo. The work supports combining RTK blockade with cytotoxic or targeted agents to prevent adaptive resistance.

  5. biorxiv.org58

    Clonally expanded CD8 T cells in AML adopt an NK-like program distinct from canonical exhaustion

    Clonally expanded CD8 T cells in newly diagnosed AML marrow are skewed toward terminally differentiated effector memory cells re-expressing CD45RA (TEMRAs), not canonical exhaustion, which was rare. In profiling 46 patients by mass cytometry plus single-cell RNA and TCR sequencing, most highly expanded clonotypes had unknown specificity and upregulated NK receptor-associated genes, defining a leukemia-associated NK-immune (LaNKi) score elevated in an independent AML dataset. This reframes AML T cell dysfunction as diverging from classical activation and exhaustion paradigms.

  6. biorxiv.org52

    Post-transcriptional dysregulation precedes morphological transformation in chemically induced liver cancer

    Post-transcriptional dysregulation is already established in histologically normal liver from DEN-exposed mice, before morphological transformation. Across 438 liver lesions from four mouse backgrounds, canonical splicing efficiency fell 3.6 to 4.8 percentage points, circRNA output rose about 2-fold with 9,718 backsplice junctions shared by all backgrounds, and A-to-I editing fell 2.2- to 3.8-fold. Paired normal liver showed tumour-like changes roughly eight months after one DEN dose, despite a median of only 337 somatic variants and no cell-cycle activation, casting these RNA changes as durable markers of damaged tissue rather than consequences of tumour growth.

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