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bioRxiv2025

Cellular heterogeneity and therapeutic response profiling of human IDH+ glioma stem cell cultures

Summary/AbstractGlioblastoma stem cell (GSC) cultures are initiated from glioblastoma (GBM) surgical resection tissue. They can capture and propagate key GBM primary tumor molecular and cellular features. We have deeply characterized four isocitrate dehydrogenase (IDH)-expressing (or IDH+) GSC cultures from unrelated adults to serve as cellular models for the majority of adult primary GBM. We demonstrate that GSC cultures can be continuously propagated in defined, serum-free media and 5% oxygen without requiring specialized growth substrates; have well-defined genomic and mtDNA variants and gene/protein expression profiles; and highly reproducible dose-survival curves when treated with the GBM standard-of-care therapies of ionizing radiation (IR) and temozolomide (TMZ). We also illustrate how expressed lentiviral barcodes, mtDNA variants and single cell gene expression profiling can be used to define and track cellular heterogeneity over 40 days after IR treatment. These well-characterized IDH+ GSC cultures can support many high throughput in vitro assay formats, including xenograft, organoid and other GBM disease modeling protocols. They should prove a useful resource to better understand GBM biology, and to identify new and more effective GBM therapies and treatment regimens. HighlightsO_LIGlioblastoma (GBM)-derived IDH-expressing Glioma Stem Cell (GSC) cultures can capture and propagate GBM genomic variants, gene and protein expression programs. C_LIO_LIMitochondrial DNA (mtDNA) variants identified by high accuracy Duplex DNA sequencing are abundant and sub-clonally organized in GSC cultures. C_LIO_LIGSC cultures have highly reproducible dose-survival curves for ionizing radiation and temozolomide, the GBM standard-of-care therapies. C_LIO_LIGSC culture cellular heterogeneity can be captured, characterized and tracked by using expressed lentiviral barcodes, mtDNA variants and scRNA sequencing. C_LI eTOC blurbIDH-expressing glioma stem cell cultures (GSCs) are experimentally tractable and versatile glioblastoma (GBM) cellular disease models. Deeply characterized GSC cultures can enable new work to understand GBM biology, and help identify new and more effective GBM therapies and treatment regimens. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/667532v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@82aceeorg.highwire.dtl.DTLVardef@1277c18org.highwire.dtl.DTLVardef@144188eorg.highwire.dtl.DTLVardef@1a84bb3_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

A minimal transcriptomic signature predicts intravascular tumor extension in renal cell carcinoma

Renal cell carcinoma (RCC) with venous tumor thrombus, termed renal intravascular tumor extension (RITE), is associated with aggressive behavior and poor clinical outcomes. Yet, its underlying molecular determinants remain incompletely defined. We analyzed RNA sequencing data from three independent RCC cohorts comprising 721 samples. Two cohorts included matched samples of index tumor, tumor thrombus, and normal adjacent kidney tissue. Analyses integrated dimensionality reduction, differential gene expression, interpretable machine learning, and gene ontology approaches. Principal component analysis revealed that only these two cohorts exhibited a coherent RITE-associated transcriptional structure. Their sequencing depth was sufficient to delineate 6,317 differentially expressed genes that distinguish RITE from non-RITE tumors. SHAP-based feature attribution across logistic regression, random forest, and XGBoost yielded a robust 29-gene consensus signature, which was further distilled into a compact 13-gene panel that preserved maximal classification performance. These genes converged on biological themes, including loss of distal epithelial identity, dysregulation of ion transport pathways, and consistent enrichment of mitochondrial processes such as oxidative phosphorylation. Together, these findings define a newly discovered and uniquely refined molecular signature of venous tumor extension in RCC and highlight mechanistically relevant pathways that may inform biomarker development and future translational strategies for predicting or mitigating RITE progression.

cancer biology↗

bioRxiv2026

PATIENT-DERIVED ORGANOIDS CAPTURE HISTOLOGICAL, MOLECULAR AND THERAPEUTIC HETEROGENEITY IN PHARYNGEAL AND LARYNGEAL SQUAMOUS CELL CARCINOMAS

BackgroundHead and neck squamous cell carcinoma (HNSCC) comprises a heterogeneous group of epithelial malignancies associated with poor survival ({approx}50%), limited therapeutic options, and a lack of predictive biomarkers. Concurrent chemoradiotherapy (CRT) remains the standard treatment for advanced disease; however, many patients fail to respond, develop resistance, or eventually relapse. The development of three-dimensional organoid technology has enabled the generation of patient-derived organoids (PDOs), offering a promising platform for personalized therapeutic testing. MethodsWe established a biobank of HNSCC PDOs from fresh laryngeal and pharyngeal tumor samples, including human papillomavirus-positive (HPV+) cases. Organoid formation and expansion rates were analyzed in relation to clinical parameters. Selected representative PDOs were histologically and molecularly characterized. Additionally, several models were exposed to cisplatin and radiation to evaluate treatment response, and a subset was assessed for tumorigenicity in subcutaneous mouse models. ResultsFifty-seven PDO models were successfully established, long-term expanded, and cryopreserved. Prior chemotherapy and/or radiotherapy was identified as an independent negative predictor of organoid outgrowth and expansion capacity compared with treatment-naive samples. Histological features, including differentiation grade and immunohistochemical markers, were largely preserved and strongly correlated with the original tumors. PDOs displayed heterogeneous responses to cisplatin and radiotherapy, with HPV-positive models showing greater sensitivity, consistent with clinical observations. Global transcriptomic profiling revealed molecular subtypes concordant with established HNSCC classifications and suggested an additional subtype characterized by low MYC and mTORC1 transcriptional activity. ConclusionHNSCC PDOs faithfully recapitulate tumor histology and molecular diversity, providing a robust platform to investigate tumor biology and therapeutic response.

cancer biology↗

bioRxiv2026

Mapping Disease Transitions from Premalignant, Asymptomatic to Advanced Myeloma through Integrative Epigenomic and Transcriptional Analyses

AbstractMultiple myeloma (MM) evolves from asymptomatic precursor conditions through progressive genetic and epigenetic remodeling, yet the regulatory mechanisms driving the development toward more active stages of the disease remain poorly understood. Here, we integrated bulk-based paired chromatin accessibility and activation, and transcriptomic profiling across disease stages to map regulatory remodeling during myeloma development. We identified a progressive increase in chromatin accessibility; furthermore, this epigenetic reconfiguration is accompanied by a stage-dependent shift from promoter-centered regulation in precursor states toward enhancer-dominated transcriptional control in active MM. Motif enrichment and regulatory network analyses identified both established and previously underappreciated transcription factors (TFs), including members of the IRF, MEF2, and FOX families, associated with disease-stage-specific transcriptional programs. Among these, MEF2D and FOXK2 emerged as candidate regulators of pathways involved in cell survival and chemotaxis. Functional perturbation demonstrated that MEF2D depletion markedly impaired MM cell viability, whereas inhibition of either MEF2D or FOXK2 reduced chemotactic migration. Together, these findings provide a stage-resolved framework of epigenetic and transcriptional remodeling across myeloma development, revealing regulatory programs established in precursor conditions and progressively reinforced during disease evolution, while identifying candidate transcriptional dependencies with potential biological and therapeutic relevance.

cancer biology↗

bioRxiv2026

Fusion-derived phospho-neoepitopes define a prioritized candidate neoantigen repertoire in MASLD-HCC

Background: The rising burden of metabolic dysfunction-associated steatotic liver disease (MASLD)-associated hepatocellular carcinoma (HCC) underscores the need for innovative therapeutic strategies. Methods: We integrated RNA-seq fusion detection, immunopeptidomics, and proteogenomics to systematically prioritize tumor-specific neoantigen candidates arising from gene fusions in MASLD-HCC. Results: We elucidated a landscape of private, clonally expressed fusions, and identified a previously unrecognized class of predicted phosphorylated fusion-neoepitopes. Cross-tumor proteomic analysis revealed that these phospho-motifs are present across malignancies, providing a broader context for their biological relevance. Importantly, fusion-positive tumors display immunosuppressive microenvironments, highlighting the need for future therapeutic strategies that combine fusion-targeted immunotherapy with approaches that overcome T-cell dysfunction. Conclusions: This study establishes a discovery pipeline and publicly available resource for fusion-derived phospho-neoepitopes in MASLD-HCC. The identified candidates provide a prioritized framework to guide and accelerate rigorous functional immunogenicity testing for future clinical validation.

cancer biology↗

bioRxiv2023

IL-1B-mediated inflammatory signaling drives ineffective erythropoiesis in early-stage myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a group of incurable hematopoietic stem cell (HSC) neoplasms characterized by peripheral blood cytopenias and a high risk of progression to acute myeloid leukemia. MDS represent the final stage in a continuum of HSCs genetic and functional alterations and are preceded by a premalignant phase, clonal cytopenia of undetermined significance (CCUS). Dissecting the mechanisms of CCUS maintenance may uncover therapeutic targets to delay or prevent malignant transformation. Here, we demonstrate that DNMT3A and TET2 mutations, the most frequent mutations in CCUS, induce aberrant HSCs differentiation towards the myeloid lineage at the expense of erythropoiesis by upregulating IL-1{beta}-mediated inflammatory signaling and that canakinumab rescues red blood cell transfusion dependence in early-stage MDS patients with driver mutations in DNMT3A and TET2. This study illuminates the biological landscape of CCUS and offers an unprecedented opportunity for MDS intervention during its initial phase, when expected survival is prolonged.

cancer biology↗

bioRxiv2024

Stratified analysis identifies HIF-2α as a therapeutic target for highly immune-infiltrated melanomas

While immune-checkpoint blockade (ICB) has revolutionized treatment of metastatic melanoma over the last decade, the identification of broadly applicable robust biomarkers has been challenging, driven in large part by the heterogeneity of ICB regimens and patient and tumor characteristics. To disentangle these features, we performed a standardized meta-analysis of eight cohorts of patients treated with anti-PD-1 (n=290), anti-CTLA-4 (n=175), and combination anti-PD-1/anti-CTLA-4 (n=51) with RNA sequencing of pre-treatment tumor and clinical annotations. Stratifying by immune-high vs -low tumors, we found that surprisingly, high immune infiltrate was a biomarker for response to combination ICB, but not anti-PD-1 alone. Additionally, hypoxia-related signatures were associated with non-response to anti-PD-1, but only amongst immune infiltrate-high melanomas. In a cohort of scRNA-seq of patients with metastatic melanoma, hypoxia also correlated with immunosuppression and changes in tumor-stromal communication in the tumor microenvironment (TME). Clinically actionable targets of hypoxia signaling were also uniquely expressed across different cell types. We focused on one such target, HIF-2, which was specifically upregulated in endothelial cells and fibroblasts but not in immune cells or tumor cells. HIF-2 inhibition, in combination with anti-PD-1, enhanced tumor growth control in pre-clinical models, but only in a more immune-infiltrated melanoma model. Our work demonstrates how careful stratification by clinical and molecular characteristics can be leveraged to derive meaningful biological insights and lead to the rational discovery of novel clinical targets for combination therapy.

cancer biology↗

bioRxiv2019

A FIJI Macro for quantifying pattern in extracellular matrix

Diverse extracellular matrix patterns are observed in both normal and pathological tissue. However, most current tools for quantitative analysis focus on a single aspect of matrix patterning. Thus, an automated pipeline that simultaneously quantifies a broad range of metrics and enables a comprehensive description of varied matrix patterns is needed. To this end we have developed an ImageJ plugin called TWOMBLI, which stands for The Workflow Of Matrix BioLogy Informatics. TWOMBLI is designed to be quick, versatile and easy-to-use particularly for non-computational scientists. TWOMBLI can be downloaded from https://github.com/wershofe/TWOMBLI together with detailed documentation. Here we present an overview of the pipeline together with examples from a wide range of contexts where matrix patterns are generated.

cancer biology↗

bioRxiv2026

Self-Supervised AI Discovery of Histomorphological Phenotypes from Routine Mesothelioma Biopsies

Accurate subtype diagnosis is essential for guiding therapy and predicting patient outcome in malignant mesothelioma. Most computational pathology models are trained on large tissue images from resection specimens, which maximises information for training but limits model relevance in real-world diagnostic settings where small biopsies are the most usual tissue source. In this work, we assembled a large multicentre cohort of HES- and HPS-stained mesothelioma biopsy slides. We used a self-supervised learning model to evaluate the associations of biopsy-driven morphology patterns with histological subtype, molecular markers, and survival. The discovered histomorphology patterns captured a continuum of tissue phenotypes spanning epithelioid, sarcomatoid, and non-tumour morphologies. Also, patient-level HPC representations achieved excellent performance for distinguishing epithelioid from non-epithelioid mesothelioma (AUC = 0.94) and demonstrated predictive value for immunohistochemistry (IHC) markers. Additionally, HPC-derived features alone achieved performance comparable to established clinical and molecular variables (C-index = 0.65), while integration of HPCs with clinical and marker information improved performance to a C-index of 0.69. Several HPCs were significantly associated with favourable or adverse prognosis and reflected known subtype-specific biological patterns. In conclusion, self-supervised learning can discover interpretable histomorphological phenotypes directly from routine mesothelioma biopsies without further training. These AI-derived phenotypes capture clinically and biologically relevant information, linking tissue architecture to molecular characteristics, histological subtypes, and patient outcomes. The proposed framework provides a thorough evaluation of real-world biopsy data using a pre-trained model, without the need for computationally intensive retraining, and addresses the question of whether SSL-based AI can be deployed out of the box in clinical settings.

cancer biology↗

bioRxiv2026

A platform for deep topographic multiomic mapping of the bone marrow environment in multiple myeloma

Multiple myeloma is a genetically complex plasma cell malignancy in which profound intratumoral heterogeneity shapes disease progression and therapeutic resistance. Genomic subclones dynamically emerge and evolve under treatment pressure, yet their spatial organization within intact bone marrow remains poorly defined. We hypothesized that genetically distinct myeloma subclones occupy spatially discrete ecological niches associated with unique molecular and microenvironmental states. To test this, we here demonstrate a proof-of-concept spatial tri-omics workflow combining laser capture microdissection-based genomics and deep LC-MS/MS proteomics with single-cell spatial transcriptomics, integrated by digital co-registration of adjacent tissue sections. Applied to a myeloma bone marrow trephine, this approach enabled coordinated profiling of matched anatomical regions demonstrating that genomic, transcriptomic and proteomic profiles converged to define clone-specific microenvironmental programmes. We show that genetically distinct myeloma subclones occupy mutually exclusive regions of the same bone marrow biopsy. Remarkably, an aggressive del(17p) clone and a gain(12q) clone occupied defined anatomical territories within the same trephine-biopsied section, each clone exhibiting distinct genomic, transcriptomic, proteomic and cellular ecosystems. The del(17p) clone localized to a fibrotic, osteolytic and angiogenic niche enriched for activated stromal cells, osteoblasts, osteoclasts and immunoregulatory myeloid populations, whereas the gain(12q) clone occupied a comparatively quiescent marrow niche with limited stromal remodelling. Together, these findings demonstrate that genetically distinct myeloma subclones establish spatially and biologically discrete ecological niches through coordinated remodelling of stromal, immune and bone compartments, providing a framework for understanding clonal evolution within the bone marrow microenvironment.

cancer biology↗

bioRxiv2023

Why does the order matters for mutations in myeloproliferative neoplasm

Certain nucleotide sequences in DNA can change their positions. Such nucleotide sequences might be shorter than a general gene. When we restrict to nucleotide sequences that form complete genes, we can still find genes that change their relative locations in a genome. Thus for different individuals of the same species, the orders of genes might be different. Such spatial difference of gene orders might be affected by temporal difference of gene (mutation) orders, and can be used to explain the order of mutation problem in myeloproliferative neoplasm. A practical problem is to determine such transposable genes in given gene sequences. Through an intuitive rule, we transform the biological problem of determining transposable genes into a rigorous mathematical problem of determining the longest common subsequence. Given several number sequences, determining the longest common subsequence is a classical problem in computer science. Depending on whether the gene sequence is linear or circular, and whether genes have multiple copies, we classify the problem of determining transposable genes into different scenarios and design corresponding algorithms. Specifically, we study the situation where the longest common subsequence is not unique.

cancer biology↗

bioRxiv2023

The expression profile and tumorigenic mechanisms of CD97 (ADGRE5) in glioblastoma render it a targetable vulnerability

Glioblastoma (GBM) is the most common and aggressive primary brain malignancy. Adhesion G protein-coupled receptors (aGPCRs) have attracted interest for their functional role in gliomagenesis and their potential as treatment targets. To identify therapeutically targetable opportunities among aGPCR family members in unbiased fashion, we analyzed expression levels of all aGPCRs in GBM and non-neoplastic brain tissue. Using bulk and single cell transcriptomic and proteomic data, we show that CD97 (ADGRE5), an aGPCR previously implicated in GBM pathogenesis, is the most promising aGPCR target in GBM, by virtue of its abundance in all GBM tumors and its de novo expression profile in GBM compared to normal brain tissue and neural progenitors. CD97 knockdown or knockout significantly reduces the tumor initiation capacity of patient-derived GBM cultures (PDGC) in vitro and in vivo. Transcriptomic and metabolomic data from PDGCs suggest that CD97 promotes glycolytic metabolism. The oncogenic and metabolic effects of CD97 are mediated by the MAPK pathway. Activation of MAPK signaling depends on phosphorylation of the cytosolic C-terminus of CD97 and recruitment of {beta}-arrestin. Using single-cell RNA-sequencing and biochemical assays, we demonstrate that THY1/CD90 is the most likely CD97 ligand in GBM. Lastly, we show that targeting of PDGCs with an anti-CD97 antibody-drug conjugate in vitro selectively kills tumor cells but not human astrocytes or neural stem cells. Our studies identify CD97 as an important regulator of tumor metabolism in GBM, elucidate mechanisms of receptor activation and signaling, and provide strong scientific rationale for developing biologics to target it for therapeutic purposes.

cancer biology↗

bioRxiv2021

Oncogenic RABL6A promotes NF1-associated MPNST progression in vivo

BackgroundMalignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that display complex molecular and genetic alterations. Powerful tumor suppressors CDKN2A and TP53 are commonly disrupted in these lesions along with NF1, a gene that encodes a negative regulator of Ras. Many additional factors have been implicated in MPNST pathogenesis. A greater understanding of critical drivers of the disease is needed to guide more informed targeted therapies for patients. RABL6A is a newly identified driver of MPNST cell survival and proliferation whose in vivo role in the disease is unknown. MethodsUsing CRISPR-Cas9 targeting of Nf1+Cdkn2a or Nf1+Tp53 in the sciatic nerve to form de novo MPNSTs, we investigated the biological significance of RABL6A in MPNST development. Molecular evaluation of terminal tumors (western blot, qRT-PCR, immunohistochemistry) yielded several insights. ResultsMice lacking Rabl6 displayed slower tumor growth and extended survival relative to wildtype animals in both genetic contexts. YAP oncogenic activity was selectively downregulated in RABL6A-null, Nf1+Cdkn2a lesions but not in RABL6A-null, Nf1+Tp53 tumors. Regardless of genetic context, loss of RABL6A caused upregulation of the CDK inhibitor, p27 in tumors. Paradoxically, both models displayed elevated Myc protein expression and Ki67 staining in terminal tumors lacking RABL6A. ConclusionsThese findings demonstrate RABL6A is required for optimal tumor progression of NF1 mutant MPNSTs in vivo in both Cdkn2a and p53 inactivated settings. However, sustained RABL6A loss may provide selective pressure for molecular alterations, such as Myc upregulation, that ultimately promote an unwanted, hyper-proliferative tumor phenotype akin to drug resistant lesions. Importance of the StudyMPNSTs are aggressive, deadly, and challenging to treat tumors due to location around nerves and high mutational burden. Many factors implicated in MPNST genesis have yet to be fully tested for biological significance in disease formation. We establish a critical physiological role for a new oncoprotein, RABL6A, in promoting NF1-associated MPNST progression. We identify novel RABL6A-regulated pathways that likely contribute to tumor growth, specifically YAP and Myc signaling, and found that sustained RABL6A loss eventually yields more proliferative tumors. We liken RABL6A deficient tumors to those being treated with therapies targeting RABL6A effectors, such as CDKs. Therefore, those lesions should provide a powerful platform to uncover key mediators of drug resistance. Our data suggest oncogenic YAP and Myc could be such mediators of resistance. This study provides a novel system to examine one of the most pressing clinical challenges, drug resistant tumor growth and relapse, in cancer therapy.

cancer biology↗

bioRxiv2019

A clinically and genomically annotated nerve sheath tumor biospecimen repository.

Nerve sheath tumors occur as a heterogeneous group of neoplasms in patients with neurofibromatosis type 1 (NF1). The malignant form represents the most common cause of death in people with NF1, and even when benign, these tumors can result in significant disfigurement, neurologic dysfunction, and a range of profound symptoms. Lack of human tissue across the peripheral nerve tumors common in NF1 has been a major limitation in the development of new therapies. To address this unmet need, we have created an annotated collection of patient tumor samples, patient-derived cell lines, and patient-derived xenografts, and carried out high-throughput genomic and transcriptomic characterization to serve as a resource for further biologic and preclinical therapeutic studies. In this work, we release genomic and transcriptomic datasets comprised of 55 tumor samples derived from 23 individuals, complete with clinical annotation. All data are publicly available through the NF Data Portal and at http://synapse.org/jhubiobank.

cancer biology↗

bioRxiv2019

GEOlimma: Differential Expression Analysis and Feature Selection Using Pre-Existing Microarray Data

BackgroundDifferential expression and feature selection analyses are essential steps for the development of accurate diagnostic/prognostic classifiers of complicated human diseases using transcriptomics data. These steps are particularly challenging due to the curse of dimensionality and the presence of technical and biological noise. A promising strategy for overcoming these challenges is the incorporation of pre-existing transcriptomics data in the identification of differentially expressed (DE) genes. This approach has the potential to improve the quality of selected genes, increase classification performance, and enhance biological interpretability. While a number of methods have been developed that use pre-existing data for differential expression analysis, existing methods do not leverage the identities of experimental conditions to create a robust metric for identifying DE genes.\n\nResultsIn this study, we propose a novel differential expression and feature selection method--GEOlimma--which combines pre-existing microarray data from the Gene Expression Omnibus (GEO) with the widely-applied Limma method for differential expression analysis. We first quantify differential gene expression across 2481 pairwise comparisons from 602 curated GEO Datasets, and we convert differential expression frequencies to DE prior probabilities. Genes with high DE prior probabilities show enrichment in cell growth and death, signal transduction, and cancer-related biological pathways, while genes with low prior probabilities were enriched in sensory system pathways. We then applied GEOlimma to four differential expression comparisons within two human disease datasets and performed differential expression, feature selection, and supervised classification analyses. Our results suggest that use of GEOlimma provides greater experimental power to detect DE genes compared to Limma, due to its increased effective sample size. Furthermore, in a supervised classification analysis using GEOlimma as a feature selection method, we observed similar or better classification performance than Limma given small, noisy subsets of an asthma dataset.\n\nConclusionsOur results demonstrate that GEOlimma is a more effective method for differential gene expression and feature selection analyses compared to the standard Limma method. Due to its focus on gene-level differential expression, GEOlimma also has the potential to be applied to other high-throughput biological datasets.

bioinformatics↗

bioRxiv2018

Connecting Patterns of Tumor Growth with Sex Differences in Extreme Survivorship for Primary Glioblastoma Patients

BackgroundSex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences.\n\nMethodsCombining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients. Pretreatment MR images of 494 glioblastoma patients (299 males and 195 females) were segmented to quantify tumor volumes. Cox proportional hazard (CPH) models and Students t-tests were used to assess which variables were associated with survival outcomes.\n\nResultsAmong males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Additionally, extent of resection, tumor laterality, and IDH1 mutation status were also found to have sex-specific effects on overall survival.\n\nConclusionDespite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes, which emphasizes the importance of considering sex as a biological factor when determining patient prognosis and treatment approach.

cancer biology↗

bioRxiv2026

Medical diagnostic radiation promotes murine Apc/Kras-driven colon carcinogenesis

Computed tomography (CT) is one of the most widely used diagnostic imaging modalities worldwide, yet the biological risks associated with such exposures remain incompletely understood. Here, we investigated the effects of clinically relevant low (25 mGy) and moderate (250 mGy) dose radiation exposures on colon carcinogenesis using in vivo KPC:APC transgenic mice and an ex vivo organoid system carrying inducible Apc and Kras driver mutations. While medical diagnostic radiation did not initiate carcinogenesis in wild-type and did not alter carcinogenesis in Apc-mutant tissues, it significantly promoted the progression of precancerous lesions in the presence of both mutations, especially when exposure occurred during early tumor initiation. Organoids derived from mice harboring both Apc and Kras mutations mirrored this susceptibility, exhibiting radiation-induced enlargement and activation of transcriptomic and proteomic programs associated with colorectal cancer, including cell-cycle dysregulation and mTORC1 pathway activation. These findings show that radiation doses within the range delivered by routine abdominal CT imaging can potentiate the carcinogenic processes in genetically predisposed cells, underscoring the need to consider individual susceptibility when evaluating the benefit-risk balance of medical diagnostic exposures.

Cancer Biology↗

bioRxiv2025

EWS-FLI1 Expression in Human Embryonic MSCs Leads to Transcriptional Reprograming, Defective DNA Damage Repair and Ewing Sarcoma

Ewing sarcoma (ES) is an aggressive bone and soft tissue neoplasm characterized by EWSR1/ETS rearrangements and whose cellular origin remains unclear. EWS-FLI1 expression in human pediatric mesenchymal stem cells (hpMSCs) induces a quantitatively and qualitatively different transcriptional response than its expression in human adult MSCs (haMSCs), but fails to form tumors in vivo. ES cells have early developmental lineage signatures distinct from postnatal MSCs. Here, we have generated MSCs from experimental teratomas out of human embryonic stem cells (heSCs). Transduction of these human embryonic mesenchymal stem cells (heMSCs) with EWS-FLI1 results in the acquisition of an ES transcriptome, although the oncogene does not preferentially bind to promoters, but to intronic and intergenic microsatellites with >10 CA dinucleotides and GGAA repeats, respectively. In heMSCs, EWS-FLI1 directly regulates BRCA1 expression, although EWS-FLI1-expressing cells show defects in DNA damage repair. Xenografting of EWS-FLI1-transduced heMSCs resulted in the formation of tumors expressing characteristic ES markers. In summary, EWS-FLI1 enforces an aberrant transcriptome and endows in vivo transforming capacity when expressed in an undifferentiated early heMSC. Our approach represents an innovative experimental method for understanding critical aspects of the biology of developmental tumors, from leukemia to sarcomas, in which few (even single) genetic alterations are able to transform a fetal stem cell.

cancer biology↗