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bioRxiv · 10.1101/2025.06.13.659489

Conserved cell state dynamics reveal targetable resistance patterns in ovarian high-grade serous carcinoma

Pirttikoski, A.·Gall-Mas, L.·Senkowski, W.·Fontaneda-Arenas, D.·Marin Falco, M.·Erkan, E. P.·Hynninen, J.·Wennerberg, K.·Vaharautio, A.
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Abstract

Core homeostatic programs of tissues, reflected in gene expression modules, can persist through oncogenesis. To reveal how cell states of normal fallopian tube epithelia (FTE) transform into intra-tumoral heterogeneity in ovarian high-grade serous carcinoma (HGSC), we applied a continuous, multi-state approach on single-cell transcriptomes of treatment-naive tumors (n=50) and normal FTE (n=14). We found the gene modules conserved from normal FTE to cancer to be more diverse than those altered during tumorigenesis, wherein the pseudotime-late TNF/NF-{kappa}B-associated module was linked to poor prognosis. The modules showed biases in subclonal structures and homologous-recombination deficiency, suggesting that genetic drivers employ existing epithelial programs for oncogenic phenotypes. Finally, organoid experiments validated actionable non-genetic drivers of these cell states, allowing chemosensitization by modulating apoptosis and NF-{kappa}B pathways. In summary, we identified prognostic, continuous cell states that reconstitute fallopian tube dynamics in HGSC and offer actionable targets to improve platinum response.

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Pirttikoski, A., Gall-Mas, L., Senkowski, W., Fontaneda-Arenas, D., Marin Falco, M., Erkan, E. P., Hynninen, J., Wennerberg, K., Vaharautio, A.. 2025-06-18. Conserved cell state dynamics reveal targetable resistance patterns in ovarian high-grade serous carcinoma. https://doi.org/10.1101/2025.06.13.659489

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