Biology subjects

Tanis, S.

Publications and source records attributed to Tanis, S..

5 recordsLinked to original sources

bioRxiv2026

Transcriptomic subtypes in high-grade serous ovarian cancer are driven by tumor cellular composition

High-grade serous ovarian carcinoma (HGSC) is an aggressive malignancy for which bulk transcriptomic subtypes are used to stratify tumors, interpret biology, and guide biomarker development. The four TCGA-derived subtypes, mesenchymal (C1.MES), immunoreactive (C2.IMM), proliferative (C5.PRO), and differentiated (C4.DIF), are consistently observed across cohorts. However, despite their prominence, these subtypes have not translated into therapeutic utility, and their biological basis remains unresolved. Here, we show that HGSC transcriptomic subtypes are largely determined by tumor cellular composition rather than intrinsic malignant transcriptional programs. By integrating controlled single-cell-derived pseudobulk simulations with deconvolution-based analysis of 1,834 primary HGSC tumors across RNA-seq and microarray cohorts, we demonstrate that subtype probabilities align along a composition-driven axis of stromal and immune variation. Cellular composition alone predicted subtype labels with high accuracy (ROC-AUC = 0.81-0.95) and explained a substantial fraction of subtype-associated transcriptomic variation, with the mesenchymal (C1.MES) subtype representing the most robust and reproducible example of composition-driven signal. Although a secondary, composition-independent expression signal is detectable, it does not define the dominant structure of subtype classification. These findings redefine HGSC transcriptomic subtypes as features of the tumor ecosystem rather than discrete malignant states. This reinterpretation has immediate implications for studies that use subtype labels to infer tumor-intrinsic biology and provides a generalizable framework for separating composition-driven and intrinsic signals in bulk tumor data. Significance StatementHGSC transcriptomic subtypes lack consistent clinical utility and remain biologically ambiguous. We show subtype assignments are largely driven by tumor cellular composition, and less so by distinct intrinsic tumor states.

cancer biology↗

bioRxiv2025

Chromosome length is not the sole determinant of sexually dimorphic crossover rates during mammalian meiosis: Insights from genetically diverse mouse strains

Meiotic recombination generates crossovers (COs), reciprocal exchanges between homologous chromosomes critical for accurate chromosome segregation. Inappropriate CO frequency and distribution drive aneuploidy in human oocytes, with error rates up to 10-fold higher than in sperm despite females exhibiting higher CO frequencies. COs form in the context of the proteinaceous synaptonemal complex (SC) that tethers homologs during prophase I. SC length strongly correlates with CO number, and sexual dimorphism in recombination has long been attributed to longer SCs in females. However, this model is challenged by wild-derived PWD mice in which males consistently generate more COs despite having shorter SCs. Here, we exploit natural genetic variation among inbred mouse strains to dissect the structural and regulatory basis of sexually dimorphic CO regulation. Using cytological markers of SC assembly (SYCP3), recombination progression (RAD51, MSH4), class I CO designation (HEI10, MLH1/MLH3), and chiasmata, we show that SC length is not the sole predictor of CO number. PWD males exhibit stronger CO interference and higher CO number than females, despite reduced SC length. Notably, females show reduced efficiency in designating recombination intermediate to become COs, whereas PWD males display exceptional proficiency. Unexpectedly, although class II COs are rare, they play a disproportionate role in ensuring that every chromosome pair receives at least one CO, thereby safeguarding against aneuploidy. Together, these findings challenge the prevailing view that SC length is the primary determinant of sexually dimorphic CO rates and instead highlight sex-specific regulation of CO designation and pathway usage as key drivers of recombination outcomes.

genetics↗

bioRxiv2025

Meiotic prophase I disruption as a strategy for non-hormonal male contraception using small-molecule inhibitor JQ1

Long-acting non-hormonal male contraceptives are urgently needed but developing strategies that are both effective and reversible presents significant challenges. Here, we investigated the potential of meiotic prophase I blockade as a promising and potentially reversible approach to male contraception. To do this, we utilized (+)-JQ1, a small-molecule inhibitor of the testis-specific protein, BRDT. Daily injections of (+)-JQ1 for three weeks resulted in disrupted spermatogenesis resulting in loss of spermatozoa and an inability to sire pups. While spermatogenic cells repopulated the testis within six weeks post drug cessation, full fertility restoration required a longer recovery period. We attribute this delay in full recovery to persistent issues with the pachytene transcriptional program, which is crucial for meiotic progression and spermatid development. These findings underscore the potential of pharmacological approaches to disrupt meiotic prophase I as a targeted, reversible male contraceptive strategy, providing new insights into developing effective non-hormonal contraceptive approaches.

cell biology↗

bioRxiv2025

Cell-state specific drug-responses are associated with differences in signaling network wiring.

Intracellular signaling pathways form networks through which information is transmitted, often in the form of kinase-mediated phosphorylation events, to interpret extracellular signals and elicit appropriate cellular responses. Yet, even isogenic cells in a homogenous environment show heterogeneity in their intracellular "cell-state", as well as their response to extracellular signals. Here, we aimed to better understand this relation between these phenomena by investigating how information flows through the EGF-receptor centered network upon targeted drug treatment, and how this is affected by cell-to-cell-state differences. Using single-cell ID-seq, we profiled the cell-state and signaling activity of primary human epidermal stem cells by measuring 69 (phospho-)proteins upon inhibition of the Erk/MAPK (p90RSK) and Akt/mTOR (p70S6K) routes downstream of the EGF pathway. We found that the effects of drug treatment propagated from the EGF-signaling pathway to other connected parts of the cellular signaling network, indicating altered signaling flow. We identified nine distinct cell-states that show pervasive state-dependent drug-responses for many (phospho-)proteins. Computational modeling of the signaling network using single-cell Comparative Network Reconstruction showed that many interactions between phospho-proteins (i.e. network wiring) were quantitatively different between cell-states. Furthermore, (phospho-)proteins with a cell-state dependent drug response, were more likely to be involved in interactions that showed a cell-state dependent strength. Overall, our results indicate that drug treatment response and signaling interactions between proteins are closely related and modulated by cell-state.

systems biology↗

bioRxiv2018

Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape

Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. In humans mutations in p63 cause several developmental disorders with defects of ectoderm-derived structures including the epidermis. The underlying molecular mechanisms of these mutations however remain unclear. Here we characterized the transcriptome and epigenome from EEC syndrome patients carrying mutations in the p63 DNA-binding domain. The transcriptome of p63 mutant keratinocytes deviated from the normal epidermal cell identity. Epigenomic analyses showed that the deregulated gene expression in p63 mutant keratinocytes resulted from an altered enhancer landscape contributed by loss of p63-bound active enhancers and by unexpected gain of enhancers. The gained enhancers in mutant keratinocytes were frequently bound by deregulated transcription factors such as RUNX1. Reversing RUNX1 overexpression partially rescued deregulated gene expression as well as the enhancer distribution. Our findings support the pivotal role of p63 in controlling the enhancer landscape of epidermal keratinocytes and identify a novel mechanism whereby p63 DNA-binding mutations associated with EEC syndrome rewire the enhancer landscape and affect epidermal cell identity.

molecular biology↗