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.
Show 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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