Molecular and spatial differences in the tumor microenvironment of high-grade serous ovarian cancers with short versus long-term survival

OBJECTIVE: Survival of patients diagnosed with advanced-stage high-grade serous ovarian cancer (HGSOC) varies widely. Understanding the biological and molecular differences between tumors associated with short-term and long-term survival may inform prognosis and treatment. METHODS: Omental tumor samples were collected from 15 short-term survivors (STS; <12 months) and 15 long-term survivors (LTS; ≥ 120 months) with stage III-IV HGSOC who underwent primary debulking surgery followed by platinum-based chemotherapy. Bulk tumor sections were analyzed using whole-genome RNA sequencing. Corresponding H&E-stained whole-slide images were processed using machine learning-based cell segmentation to identify cell phenotypes. Computational image analysis was used to extract morphometric features. The integrated transcriptomic and image-derived data were used to quantify proportions of cancer cells, fibroblasts, and immune cells, and to identify differences in nuclear texture, cancer cell spatial organization, and collagen architecture. RESULTSS: STS was associated with higher fibroblast content (48.6% vs 33.5%, p < 0.05), lower cancer cell content (48.0% vs 64.3%, p < 0.05), and a lower tumor-fibroblast proportion (0.9 vs 1.8, p < 0.05) than LTS. Computational image analyses identified significant differences in nuclear texture, cancer cell spatial organization, and collagen architecture. STS correlated with upregulation of fibroblast-associated genes (ITGAV, p < 0.05; INHBA, p < 0.0001) and epithelial-mesenchymal transition markers (ZEB1, p < 0.001; CALD1, p < 0.001), while LTS was enriched for immune signaling pathways. CONCLUSIONS: Omental metastases from STS and LTS patients have distinct molecular and spatial profiles. The enrichment of fibroblast-associated gene signatures in STS and immunoreactive pathways in LTS underscores a divergent tumor microenvironment with potential clinical relevance.