Abstract Background: Women of African ancestry are disproportionately affected by high-grade serous ovarian cancer (HGSOC), experiencing earlier onset, more aggressive disease, and poorer outcomes compared to women of European ancestry. While socioeconomic and access-related factors contribute to these disparities, the role of ancestry-associated tumor biology and microenvironment remains underexplored. This study integrates multi-omics and spatial profiling to identify molecular and cellular determinants of HGSOC disparities across diverse ancestral backgrounds. Methods: The cohort consists of HGSOC tissues from n= 35 cases of African ancestry (West African Born, Caribbean Born Black, and US Born) and n=14 cases European ancestry (US- white). A tissue microarray representing 3–4 cores per case was constructed. NanoString GeoMx Digital Spatial Profiling was used to assess protein and transcript expression across tumor (PanCK+), immune (CD45+), and stromal (PanCK-/CD45-) compartments. CosMx Spatial Molecular Imager enabled subcellular-resolution transcriptomics across 900,000 cells and 11 cell types. CellChat was used to infer ancestry-specific ligand–receptor signaling networks and intercellular communication patterns. Results: The mean age at diagnosis was lowest in WAB (51.7 ± 12.8 years) and highest in USW (65.0 ± 13.4 years). GeoMx DSP revealed moderate transcript–protein concordance (R 0.4) in 35% of targets, with the TIME compartment exhibiting the highest number of differentially expressed genes. USW tumors were enriched for humoral immune programs, plasma cell activity, and epithelial/developmental markers—signatures associated with favorable prognosis and predicted responsiveness to immune checkpoint blockade. CBB tumors displayed robust ECM remodeling, complement-driven immunity, and phosphatase/proteostasis activity—indicative of a desmoplastic, treatment-resistant phenotype potentially amenable to ECM- or complement-targeted therapies. WAB tumors were characterized by Wnt signaling, epithelial adhesion, and metabolic stress responses, aligning with early onset, chemoresistant disease biology. CosMx analysis revealed a shared fibroblast–macrophage scaffold across all cohorts, with ancestry-specific signals: CBB tumors emphasized collagen/laminin and MIF–CD74 loops; WAB tumors showed self-adhesion (CDH1, CLDN3) and IGF2–IGF1R axis activity; USW tumors exhibited proliferative and developmental signaling (IGF1R, NOTCH, LRP1); USB tumors retained the core scaffold but uniquely engaged VEGFA–VEGFR angiogenic signaling. Conclusions: Our integrative spatial and molecular profiling reveals four ancestry-associated tumor ecosystems in HGSOC, each with distinct immune, stromal, and developmental features. These findings support the existence of biologically distinct HGSOC subtypes linked to ancestry and underscore the need for ancestry-informed therapeutic strategies to reduce disparities in ovarian cancer outcomes. Citation Format: Ayodele Omotoso, Alex Covarrubias-Sanchez, Jovanka Ravix, Osmaray Morales, Fatima Rasheed, Maurice Junior Chery, Lauren Smith, Daniela Betancur, Ivana Sorbit, Melissa Castillo, Destiny Burnett, Sandy St-Hillare, Elizabeth Smith Smith, Olugbenga Akindele. Silas, Emmanuel Kunle. Abudu, Suleiman Dauda, Adeyemi Okunowo, Patience Odusolu, Theophilus Ugbem, Murtala Abubakar, Saida Bowe, Uchenna Ezenkwa, Aisha Mustapha, Raleigh Butler, Matthew Schlumbrecht, Bala Audu, Saad Ahmed, Andre Pinto, Sophia George, Darron Halliday, Caryn Sands, George Bruney, Anupama Jacob, Michael Tanimowo. Multi-Omics profiling of high-grade serous ovarian cancer reveals ancestry-associated molecular and tumor microenvironmental differences abstract. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C041.
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