NF-κB–mediated chemoresistance emerges from distorted fallopian tube cell-state trajectory in ovarian cancer

Abstract Homeostatic gene expression programs persist through oncogenesis, creating new malignant states that adapt to therapies. To reveal how fallopian tube epithelia (FTE) cell states transform into intra-tumoral heterogeneity in ovarian high-grade serous carcinoma (HGSC), we analysed treatment-naive tumors ( n = 50) and normal FTE ( n = 14) by single cell transcriptomics, identifying tissue-specific transcriptional modules gained, lost, or conserved through carcinogenesis. Of these, two conserved, opposing modules associated with survival and showed genetic biases, suggesting that oncogenic drivers employ existing epithelial programs. Challenging the cancer stem cell paradigm, a developmentally early oxidative-phosphorylation module was associated with improved survival, whereas the developmentally late MAPK/NF-κB module defined a stable, chemoresistant state that had lost the MHC II antigen presentation of the corresponding normal FTE state. Using these modules to predict perturbations capable of shifting cell-state dynamics, we demonstrate in patient-derived organoid models that restraining ER stress via SERCA2 activation drives a resistant, NF-κB–active phenotype, whereas inhibiting the DNA repair regulator CCDC6 promotes the opposite, platinum-sensitive state. Our study suggests that conserved tissue-of-origin states, rather than de novo cancer states, drive the key cell state dynamic and clinical response heterogeneity of HGSC and can be targeted in vitro to modulate platinum response.