Multiplex organoid mutagenesis reveals gene combinations driving transformation, pathology and chemosensitivity in ovarian carcinoma

Transcriptomic analysis revealed that tumors bearing Nf1 mutations overexpressed the long non-coding RNA Pvt1, a marker associated with poor prognosis in HGSC patients, regardless of pathological phenotype Map2k4-mutant organoids were more sensitive to paclitaxel and niraparib, while Nf1-mutant combinations responded better to trametinib. Notably, the removal of Rho kinase inhibitor (ROCKi) reduced trametinib sensitivity in both Map2k4- and Nf1-mutant organoids, underscoring the importance of culture conditions and potential antagonistic drug interactions in organoid-based drug screens.

Collectively, our results demonstrate that TE-derived organoids coupled with combinatorial CRISPR mutagenesis provide a powerful system to unravel the genetic and phenotypic complexity of HGSC. In particular, we found that Map2k4 functions as a tumor suppressor that shapes distinct tumor histology and chemosensitivity, suggesting it as a potential therapeutic target in select HGSC cases.