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bioRxiv2022

Design, synthesis and biological evaluation of novel quercetin derivatives as PPAR-γ partialagonists by modulating Epithelial-mesenchymal transition in lung cancer metastasis

Epithelial-to-mesenchymal transition (EMT) is responsible for driving metastasis of multiple cancer types including lung cancer. Peroxisome proliferator-activated receptor (PPAR)-{gamma}, a ligand-activated transcription factor, controls expression of variety of genes involved in EMT, cellular differentiation, fatty acid metabolism, insulin sensitivity and adipogenesis. Several synthetic compounds act as potent full agonist for PPAR-{gamma}. However, owing to their serious adverse effects, restricts their long-term application. Therefore, partial agonist has been greatly in demand which involves reduced and balanced PPAR-{gamma} activity. Our previous study discerned the efficacy of quercetin and its derivatives to attain favourable stabilization with PPAR-{gamma}. Here we extended this work by synthesizing five novel quercetin derivatives (QDs) namely thiosemicarbazone (QUETSC) and hydrazones (QUEINH, QUENH, QUE2FH and QUESH) and analysed their effects in modulating EMT of lung cancer cell lines via PPAR-{gamma} partial activation. QDs-treated A549 cells exhibited cell death strongly in a dose and time dependent manner at nanomolar concentration along with anti-migratory effects compared to NCI-H460 cells. Of the five derivatives we screened, QUETSC, QUE2FH and QUESH exhibited the property of partial activation as compared to the over-expressive level of rosiglitazone (RSG). Consistently, with PPAR-{gamma} partial activation, these QDs also suppressed EMT process by markedly down-regulating the levels of mesenchymal markers (Snail, Slug and Zeb-1) and concomitant up-regulation of epithelial marker (E-cadherin). In the light of these evidences; QUETSC, QUE2FH and QUESH could be used as a novel selective partial PPAR-{gamma} modulators whose pharmacological properties is distinct from RSG and may be exploited as potential therapeutic anti-metastatic agent.

cancer biology↗

bioRxiv2025

Patient-Specific Pharmacogenomics unveils xCT Regulation Pathways in Colon Cancer

Colorectal cancer (CRC) represents the third-leading cause of cancer-related deaths. Knowledge covering diverse cellular and molecular data from individual patients has become valuable for diagnosis, prognosis, and treatment selection. Here, we present an in-depth comparative mRNA-seq and microRNA-seq analysis of tissue samples from 32 CRC, pairing tumors with adjacent healthy tissues. The differential expression gene (DEG) analysis revealed an interconnection between nutrients, metabolic programs, and cell cycle pathways. We focused on the impact of overexpressed SLC7A11 (xCT) and SLC3A2 genes which compose the cystine/glutamate transporter (Xc-) system. To assess the oncogenic potency of the Xc-system in a cellular setting, we applied a knowledge-based approach for analyzing gene perturbations from CRISPR screens across various cell types as well as using a variety of functional assays in five primary patient-derived organoid cell models to functionally verify our hypothesis. We identified a previously undescribed cell surface protein signature predicting chemotherapy resistance and further highlighted the causality and potential of pharmacological blockage of ferroptosis as promising avenue for cancer therapy. Biological processes such as redox homeostasis, ion/amino acid transporters and de novo nucleotide synthesis were associated with these co-dependent genes in patient specimens. This study highlighted a number of overlooked genes as potential clinical targets for CRC and promotes stem cell-based, patient-individual in vitro model systems as a versatile partner platform to functionally validate in silico predictions, with focus on SLC7A11 and its associated genes in tumorigenesis.

cancer biology↗

bioRxiv2022

Influence of genetic ancestry on breast stromal cells provides biologic basis for increased incidence of metaplastic breast cancer in women of African descent

The biologic basis of genetic ancestry-dependent variability in disease incidence and outcome is just beginning to be explored. We recently reported enrichment of a population of ZEB1-expressing cells located adjacent to the ductal epithelial cells in the normal breast of women of African Ancestry (AA) compared to European Ancestry (EA). By establishing and characterizing cell lines corresponding to these cells and validating in vitro findings with tissue microarrays of healthy breast tissue from AA, EA and Latina Ancestry (LA) women, we demonstrate that these cells have the properties of fibroadipogenic/mesenchymal stromal cells that express PROCR and PDGFR. PROCR+/ZEB1+/PDGFR+ cells, hence renamed as PZP cells, are enriched in the normal breast tissues of AA compared to EA or LA women. In vitro, PZP cells trans-differentiated into adipocytes or osteocytes. In co-culture conditions, PZP:epithelial cell communication resulted in luminal epithelial cells acquiring basal/stem cell characteristics and increased expression of IL-6 suggesting the impact of this communication on breast epithelial hierarchy and the microenvironment. Consistent with this possibility, the level of phospho-STAT3, which is a downstream target of IL-6, was higher in the normal and cancerous breast tissues of AA compared to EA women. PZP cells transformed with HRasG12V {+/-} SV40-T/t antigens generated metaplastic carcinoma in NSG mice suggesting that these cells could be the cell-of-origin of metaplastic breast cancers. Collectively, these results identify a stromal cell component that could influence the biology of breast cancer in AA women.

cancer biology↗

bioRxiv2025

BMI-1 Modulation and Trafficking During M Phase in Diffuse Intrinsic Pontine Glioma

BMI-1 (B cell-specific Moloney murine leukemia virus integration site 1) has been implicated in both normal and cancer cell biology. While the canonical function of BMI-1 involves epigenetic repression, novel extra-nuclear functions have been recently reported. In the present study, we demonstrate that the phosphorylation of BMI-1 in diffuse intrinsic pontine glioma (DIPG) cells occurs in M phase and that triggers simultaneous translocation of the phosphorylated BMI-1 to the cytoplasm. This translocation is mediated by the RanGTP-dependent transporter CRM1, also known as exportin. Furthermore, we uncovered a previously unidentified nuclear export signal (NES) in BMI-1 protein, suggesting an active transport type of modified BMI-1 mediated by CRM1. These findings associate BMI-1 phosphorylation with its trafficking in M phase. Collectively, this study sheds light on the molecular mechanisms underlying BMI-1 functions in DIPG, thereby potentially paving the way for the development of targeted therapeutic strategies related to M phase progression.

cancer biology↗

bioRxiv2026

Benchmarking scRNA-seq Copy Number Inference: A Comprehensive Evaluation and Practitioner Guide

Accurately inferring copy number variation (CNV) from scRNA-seq data is critical for identifying malignant cells, reconstructing tumor subclonal architecture, and uncovering the genomic drivers that dictate cancer cell biology. However, the performance of existing tools varies significantly, and current benchmarks lack the breadth of datasets and methods necessary to provide definitive guidance. We present a comprehensive benchmark of 12 CNV inference methods across 28 real datasets (>100,000 cells) and diverse synthetic datasets. By evaluating methods based on malignant cell classification accuracy, CNV inference accuracy, scalability, and robustness, we establish a definitive practitioners guideline: allele-aware methods like Numbat excel when high-quality allelic inference can be achieved, whereas expression-centric tools such as Clonalscope, CopyKAT, inferCNV, and SCEVAN remain reliable when raw sequencing data are unavailable. Our study provides both a practical decision-making framework for researchers and a public repository of standardized CNV profiles to catalyze further methodological innovation.

cancer biology↗

bioRxiv2026

Impact of the sphingolipid metabolizing enzyme β-galactosylceramidase on mitochondrial sphingolipid profile and energetic metabolism in human melanoma cells

Mitochondrial plasticity, characterized by the dynamic balance between glycolysis and oxidative phos-phorylation in response to genetic and microenvironmental changes, is a hallmark of melanoma progression. Sphingolipids play a significant role in various aspects of cancer cell biology, including metabolic reprogramming. Previous observations had shown that the lysosomal sphingolipid-metabolizing enzyme {beta}-galactosylceramidase (GALC) rewires the lipid profile of mouse melanoma cells, exerting pro-oncogenic functions, gene silencing leading to a decreased oncogenic activity in murine and human melanoma cells. Here, we have focused on the mitochondrial sphingolipid composition and energetic metabolism in GALC knockout (KO) A2058 human melanoma cells. Targeted analysis of the mitochondrial sphingolipid profile, transcriptomic data, and mitochondrial structural and functional studies indicate that GALC loss drives a sphingolipid-mediated reprogramming of mitochondrial metabolism in absence of major structural alterations, characterized by bioenergetic insufficiency possibly due to ceramide- and sphingomyelin-driven impairment of respiratory chain function. Overall, these data indicate that GALC KO leads to a sphin-golipid-driven mitochondrial metabolic suppression and may provide novel information for the development of efficacious approaches in mitochondrial targeting melanoma therapies.

cancer biology↗

bioRxiv2024

Differentially expressed growth factors and cytokines drive phenotypic changes in transmissible cancers

The Tasmanian devil is threatened by two deadly transmissible Schwann cell cancers. A vaccine to protect Tasmanian devils from both devil facial tumour 1 (DFT1) and devil facial tumour 2 (DFT2), and improved understanding of the cancer cell biology, could support improved conservation actions. Previous transcriptomic analysis has implicated phenotypic cellular plasticity as a potential immune escape and survival mechanism of DFT1 cells. This phenotypic plasticity facilitates transition from a myelinating Schwann cell to a repair Schwann cell phenotype that exhibits mesenchymal characteristics. Here, we have identified cytokines and growth factors differentially expressed across DFT cell phenotypes and investigated their role in driving phenotypic plasticity and oncogenic properties of DFT cells. Our results show that NRG1, IL16, TGF{beta}1, TGF{beta}2 and PDGFAA/AB proteins have significant and distinct effects on the proliferation rate, migratory capacity and/or morphology of DFT cells. Specifically, PDGFR signalling, induced by PDGFAA/AB, was a strong enhancer of cell proliferation and migration, while TGF{beta}1 and TGF{beta}2 induced epithelial-mesenchymal transition (EMT)-like changes, inhibited proliferation and increased migratory capacity. These findings suggest complex interactions between cytokine signalling, phenotypic plasticity, growth and survival of DFTs. Signalling pathways implicated in the propagation of DFT are potential targets for therapeutic intervention and vaccine development for Tasmanian devil conservation.

cancer biology↗

bioRxiv2025

Hyperlipidemia drives tumor growth in a mouse model of obesity-accelerated breast cancer growth.

Obesity is an established risk factor for breast cancer (BC), yet the specific mechanisms driving this association remain unclear. Dysregulated lipid metabolism has emerged as a key factor in cancer cell biology. While obesity is often accompanied by hyperlipidemia, the isolated impact of elevated lipid levels on BC growth has not been experimentally tested. Using the E0771 orthotopic model of obesity-accelerated BC growth in immune-competent mice, we investigated the direct role of systemic lipids in tumor growth. Combining dietary and genetic mouse models, we show that elevated circulating lipids are sufficient to accelerate BC tumor growth even in the absence of obesity or alterations in blood glucose and/or insulin levels. Pharmacological lowering of systemic lipid levels attenuates BC growth in obese mice, suggesting a direct role for lipids in fueling tumor expansion. Notably, we also show that weight loss alone, without a corresponding reduction in lipid levels such as that induced by a ketogenic diet, fails to protect against BC, highlighting the necessity of targeting lipid metabolism in obesity-associated BC. Our findings establish hyperlipidemia as a critical driver of BC progression and suggest that lipid-lowering interventions may be a promising strategy to mitigate BC risk in obese individuals.

cancer biology↗

bioRxiv2026

Subgroup-Specific Associations of GRIA Genes Encoding AMPA Glutamate Receptor Subunits with Patient Survival in Medulloblastoma

Brain cancers hijack biological systems involved in neural development and synaptic plasticity. Medulloblastoma (MB), the most common malignant brain tumor in children, is thought to arise from disruptions in neurodevelopmental programs. Glutamatergic transmission mediated by -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) has been implicated in synaptic communication between adult brain tumors and surrounding neurons; however, the possible role of AMPARs in MB remains largely unexplored. Here, we analyzed the expression of genes encoding AMPAR subunits, GRIA1-4, in datasets of MB tumor and cell lines, revealing distinct expression patterns and associations with overall survival (OS) across molecular subgroups and histological variants. Expression levels differed among MB molecular subgroups. Analysis using single-cell RNA sequencing (scRNA-seq) was consistent with enrichment of GRIA1 in Group 3 and GRIA4 in SHH MB. Higher GRIA1, GRIA2, and GRIA4 transcription was associated with more favorable patient outcomes in specific MB subgroups. In contrast, high expression of GRIA3 in SHH, or of either GRIA3 or GRIA4 in Group 3 MB, was associated with worse prognosis. Particularly robust but opposing associations with patient survival were found for GRIA3 and GRIA4 in SHH MB. Analysis of GRIA mRNA levels in MB cell lines using both quantitative reverse transcription polymerase chain reaction (qRT-PCR) and data from The Human Protein Atlas, supported some of the gene expression patterns observed in tumors. Together, these findings suggest that GRIA genes and their corresponding AMPAR subunits may have subgroup-specific prognostic relevance in MB.

cancer biology↗

bioRxiv2016

Mutation signatures reveal biological processes in human cancer

Replication errors in the genome accumulate from a variety of mutational processes, which leave a history of mutations on the affected genome. The relative contribution of each mutational process has been characterized by non-negative matrix factorization and has lead to deeper insight into both mutational and repair processes contributing to cancer. However current implementations of NMF have left unresolved some specific patterns that should be present in the mutation data and have not generated signatures designed for classification. Here, we use a variant of NMF, termed non-smooth NMF, to generate sparse matrix factorizations of somatic mutation profiles present in 7129 tumors. nsNMF factorization revealed 21 mutational signatures. We found three APOBEC mutational processes clearly segregating with the published APOBEC enzymology and trans-lesion repair processes. We discovered several signatures differed between geographic locations even between closely related tissues.

Genomics↗

bioRxiv2021

Network Analysis Reveals Synergistic Genetic Dependencies for Rational Combination Therapy in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia

Systems biology approaches can identify critical targets in complex cancer signaling networks to inform therapy combinations and overcome conventional treatment resistance. Herein, we developed a data-driven, network controllability-based approach to identify synergistic key regulator targets in Philadelphia chromosome-like B-acute lymphoblastic leukemia (Ph-like B-ALL), a high-risk leukemia subtype associated with hyperactive signal transduction and chemoresistance. Integrated analysis of 1,046 childhood B-ALL cases identified 14 dysregulated network nodes in Ph-like ALL involved in aberrant JAK/STAT, Ras/MAPK, and apoptosis pathways and other critical processes. Consistent with network controllability theory, combination small molecule inhibitor therapy targeting a pair of key nodes shifted the transcriptomic state of Ph-like ALL cells to become less like kinase-activated BCR-ABL1-rearranged (Ph+) B-ALL and more similar to prognostically-favorable childhood B-ALL subtypes. Functional validation experiments further demonstrated enhanced anti-leukemia efficacy of combining the BCL-2 inhibitor venetoclax with tyrosine kinase inhibitors ruxolitinib or dasatinib in vitro in human Ph-like ALL cell lines and in vivo in multiple patient-derived xenograft models. Our study represents a broadly-applicable conceptual framework for combinatorial drug discovery, based on systematic interrogation of synergistic vulnerability pathways with pharmacologic targeted validation in sophisticated preclinical human leukemia models.

cancer biology↗

bioRxiv2021

Mechanistic model: Analysis of diffusion dynamics of Lugol's chromoendoscopy in Basal layer-type squamous cell carcinoma in situ via Euler's method and Law of mass action

Basal layer-type squamous cell carcinoma in situ(BLSCC) is an aggressive malignancy tumor. In the past, it usually went ignored because its aggressive biological behavior is different from typical esophageal squamous cancer(SCC). For our mechanistic model, we analyzed diffusion dynamics of iodine stain in BLSCC with the help of Eulers method. We used the law of mass action description of the forming process of the iodine-glycogen Complex. Based on the above analysis, our mechanistic model reveals that the efficacy of Lugols chromoendoscopy is determined by the thickness of the squamous epithelial cell layer, which contains glycogen granules, and the convection of the interpupillary capillary loop(IPCL). A further inference can be made: the unique histological structure of BLSCC suggests Lugols chromoendoscopy does not detect some components of it because these components neither break enough squamous epithelial cells which contain glycogen granules nor contain enough number of IPCL in a specific time frame. Besides, if our mechanistic model starting point is BLSCC and typical SCC share the same evolution path, we found both their cytoplasm tends to solid phase from the iodine diffusion dynamics analysis in "pink color sign."

cancer biology↗

bioRxiv2022

Phylovar: Towards scalable phylogeny-aware inference of single-nucleotide variations from single-cell DNA sequencing data

Single-nucleotide variants (SNVs) are the most common variations in the human genome. Recently developed methods for SNV detection from single-cell DNA sequencing (scDNAseq) data, such as SCI{Phi} and scVILP, leverage the evolutionary history of the cells to overcome the technical errors associated with single-cell sequencing protocols. Despite being accurate, these methods are not scalable to the extensive genomic breadth of single-cell whole-genome (scWGS) and whole-exome sequencing (scWES) data. Here we report on a new scalable method, Phylovar, which extends the phylogeny-guided variant calling approach to sequencing datasets containing millions of loci. Through benchmarking on simulated datasets under different settings, we show that, Phylovar outperforms SCI{Phi} in terms of running time while being more accurate than Monovar (which is not phylogeny-aware) in terms of SNV detection. Furthermore, we applied Phylovar to two real biological datasets: an scWES triple-negative breast cancer data consisting of 32 cells and 3375 loci as well as an scWGS data of neuron cells from a normal human brain containing 16 cells and approximately 2.5 million loci. For the cancer data, Phylovar detected somatic SNVs with high or moderate functional impact that were also supported by bulk sequencing dataset and for the neuron dataset, Phylovar identified 5745 SNVs with non-synonymous effects some of which were associated with neurodegenerative diseases. We implemented Phylovar and made it publicly available at https://github.com/mae6/Phylovar.git.

cancer biology↗

bioRxiv2022

Genomic analyses identify significant molecules and biological processes in colorectal cancer cells with DNA damage

Colorectal cancer is a major cause of cancer deaths in the US. DNA damage is considered to be a novel target for the treatment of colorectal cancer. However, the molecular mechanisms and functions are still unclear. In this study, we aim to identify the significant molecules and signaling by analyzing the RNA-seq data. The GSE189366 was created by the BGISEQ-500 (Homo sapiens). The KEGG and GO analyses indicated the p53 signaling pathway and Hippo signaling pathway are major affected processes in colorectal cancer by DNA damage. Furthermore, we identified ten key interactive molecules including CDK1, STAT3, MDM2, CCNB1, CCNA2, CDKN1A, PCNA, AURKA, PLK1, and CDC6. Our study may provide potential drug targets for colorectal cancer.

bioinformatics↗

bioRxiv2023

maGENEgerZ: An Efficient AI-Based Framework Can Extract More Expressed Genes and Biological Insights Underlying Breast Cancer Drug Response Mechanism

Understanding breast cancer drug response mechanism can play a crucial role in improving the treatment outcomes and survival rates. Existing bioinformatics-based approaches are far from perfect and do not adopt computational methods based on advanced artificial intelligence concepts. Therefore, we introduce a novel computational framework based on an efficient support vector machines (esvm) working as follows. First, we downloaded and processed three gene expression datasets related to breast cancer responding and non-responding to the treatments from the gene expression omnibus (GEO) according to the following GEO accession numbers: GSE130787, GSE140494, and GSE196093. Our method esvm is formulated as a constrained optimization problem in the dual form as a function of {lambda}. We recover the importance of each gene as a function of {lambda}, y, and x. Then, we select p genes out of n, provided as input to enrichment analysis tools, Enrichr and Metascape. Compared to existing baseline methods including deep learning, results demonstrate superiority and efficiency of esvm achieving high performance results and having more expressed genes in well-established breast cancer cell lines including MD-MB231, MCF7, and HS578T. Moreover, esvm is able to identify (1) various drugs including clinically approved ones (e.g., tamoxifen and erlotinib); (2) seventy-four unique genes (including tumor suppression genes such as TP53 and BRCA1); and (3) thirty-six unique TFs (including SP1 and RELA). These results have been reported to be linked to breast cancer drug response mechanism, progression, and metastasizing. Our method is available publicly in the maGENEgerZ web server at https://aibio.shinyapps.io/maGENEgerZ/.

bioinformatics↗

bioRxiv2024

SOX21 suppresses GBM growth by repressing AP-1 regulated target genes

BackgroundTreatment-resistant glioblastoma stem cells (GSCs) drive glioblastoma (GBM) growth and recurrence. Thus, targeting the molecular machinery that sustains GSCs in an undifferentiated and self-renewing state is a promising therapeutic strategy. The transcription factor SOX21 effectively suppresses the tumorigenic capacity of GSCs. However, the mechanism by which SOX21 impedes GSC features is unknown. MethodsPatient-derived GSCs were engineered with a transgenic TetOn system to enable inducible expression of SOX21 or appropriate controls. The capacity of SOX21 to incapacitate GSCs was assessed using in vitro cell culture models and orthotopic mouse models. Cellular and genome-wide techniques, including RNA-seq, ChIP-seq, and ATAC-seq, were employed to examine the mechanisms by which SOX21 regulates GSCs. ResultsWe show that SOX21 expression in primary GSCs induces an anti-tumorigenic transcriptional program, aligning with clinical data showing a positive correlation between SOX21 levels and improved GBM patient survival. Induced SOX21 expression in GSCs within pre-established GBM reduces their capacity to sustain tumor growth and significantly extends the survival of the transplanted mice. Mechanistically, SOX21 functions as a tumor suppressor by binding a large set of AP-1-targeted chromatin regions, leading to epigenetic repression of AP-1-activated genes that support GSC survival and proliferation. Consistently, the anti-tumorigenic activities of SOX21 are replicated by AP-1 inhibitors, while overexpression of the AP-1 family member, c-JUN, counteracts these effects. ConclusionOur findings identify SOX21 as a key regulator that prevents GSC malignancy by targeting and repressing an AP-1-driven, tumor-promoting gene expression program. These results highlight SOX21-regulated pathways as promising therapeutic targets for GBM. Key PointsO_LIInduced SOX21 expression suppresses GSCs and inhibits the growth of established GBM C_LIO_LISOX21 acts as a tumor suppressor in GSCs by directly repressing AP-1-driven genes C_LIO_LIPharmacological inhibition of AP-1 mimics SOX21 activity in GSCs C_LI Importance of the StudyGBM is the most common and aggressive malignant brain tumor in adults. Recurrence following treatment often stems from the failure of therapeutic interventions to effectively target GSCs, which serve as the primary reservoir for tumor regrowth. The resilience of GSCs to treatment is partly due to the inactivation of intrinsic tumor suppressor programs that would otherwise direct GSCs to cellular senescence and death. This study demonstrates that increased expression levels of the tumor suppressor SOX21 in pre-established GBM disrupt tumor progression by disabling self-renewing GSCs. We show that SOX21 exerts its tumor-suppressive function by targeting and repressing an AP-1-driven gene network, which is a key regulator of GSC maintenance and proliferation. By uncovering the molecular mechanisms through which SOX21 controls GSC biology, our findings provide valuable insights for basic cancer research and may inform the development of novel therapeutic strategies for GBM.

cancer biology↗

bioRxiv2019

Sex Differences in Mutational Processes

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here, we describe the first pan-cancer analysis of sex differences in whole genomes of 1,983 tumours of 28 subtypes from the ICGC Pan-Cancer Analysis of Whole Genomes project. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in cancer research. Sex disparities in cancer epidemiology include an increased overall cancer risk in males corresponding with higher incidence in most tumor types, even after adjusting for known risk factors1,2. Cancer mortality is also higher in males, due in part to better survival for female patients in many cancer types, including those of the colon and head & neck3. Interestingly, female colorectal cancer patients respond better to surgery4 and adjuvant chemotherapy, though this is partially due to biases in tumour location and microsatellite instability5. Similarly, premenopausal female nasopharyngeal cancer patients have improved survival regardless of tumour stage, radiation or chemotherapy regimen6. There is a growing body of evidence for sex differences in cancer genomics7-13, but their molecular origins and clinical implications remain largely elusive. Previous studies have mostly focused on protein coding regions, leaving the vast majority of the genome unexplored. We hypothesized that there are uncharacterized sex differences in the non-coding regions of the genome. Using whole genome sequencing data from the Pan-cancer Analysis of Whole Genomes (PCAWG) project14, we performed a survey of sex-biased mutations in 1,983 samples (1,213 male, 770 female) from 28 tumour subtypes, excluding those of the sex organs (Supplementary Table 1). We also excluded the X and Y chromosomes to focus on autosomal sex differences in cancers affecting both men and women, but there are known to be significant X-chromosome mutational differences between tumours arising in men and women15. Our analysis revealed sex differences in both genome-wide phenomena and in specific genes. These sex-biases occur not only at the pan-cancer level across all 1,983 samples, but also in individual tumour subtypes.

cancer biology↗

bioRxiv2024

An ALK1-governed monocytic lineage shapes an immunosuppressive landscape inbreast cancer metastases

The biology centered around the TGF-{beta} type I receptor ALK1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipated Acvrl1 expression, are effector targets for adjuvant anti-angiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the release of CD14+ monocytes into circulation, and their eventual extravasation. Notably, ACVRL1+ TAMs coincided with an immunosuppressive phenotype, and were over-represented in human cancers progressing on therapy. Accordingly, breast cancer patients with a prominent ACVRL1hi TAM signature exhibited a significantly shorter survival. In conclusion, we shed light on an unexpected multimodal regulation of tumorigenic phenotypes by ALK1 and demonstrate its utility as a target for anti-angiogenic immunotherapy. Graphical abstractSee submitted file

cancer biology↗