Compartment-Resolved Profiling Identifies Shared Stromal Programs and Clarifies Molecular Subtype Origins in Ovarian Cancer

Epithelial ovarian cancers (EOCs) comprise biologically distinct histotypes that arise within shared anatomical niches where tumor–stroma interactions shape tumor behavior and therapeutic response. However, most classification frameworks rely on bulk profiling that conflates epithelial and stromal contributions, limiting the understanding of crosstalk between the different compartments. Here, we performed compartment-resolved transcriptomic and epigenomic profiling of matched carcinoma and stroma across clear cell (CCOC), endometrioid (ENOC), and high-grade serous ovarian cancers (HGSC). Carcinoma profiles segregated strongly by histotype, whereas stromal profiles showed minimal histotype specificity and instead resolved into four shared groups (S1–S4). The S4 subtype, marked by a desmoplastic, myofibroblast-rich program, was enriched in omental tumors and corresponded to the HGSC C1/Mesenchymal signature. This subtype largely reflected tumor-extrinsic programs and was present beyond HGSC. Compartment-resolved analyses also refined the interpretation of other molecular carcinoma subtypes and revealed distinct carcinoma-intrinsic EMT-like programs. Together, these findings define a histotype-agnostic stromal architecture across epithelial ovarian cancers, clarify the cellular basis of canonical high-grade serous molecular subtypes, and reveal carcinoma-intrinsic EMT programs. This study underscores the value of physically separating epithelial and stromal compartments before molecular analysis and position this dataset as a multi-purpose reference resource for the EOC research community.