Abstract B030: Ablation of hematopoietic stem cell derived adipocytes reduces tumor burden in syngeneic mouse models of ovarian cancer

Abstract Adipose tissue supports ovarian cancer progression, but the contribution of adipose cells of non-mesenchymal origin has been underappreciated. In this study, we examine hematopoietic stem cell-derived adipocytes (HSCDAs) and their differences from conventional mesenchymal adipocytes (CMAs) in the context of high-grade serous carcinoma (HGSC). We acquired adipose precursor cells from subcutaneous human adipose biopsies. We found that differentiating HSCDAs and CMAs accumulated lipid droplets at a similar rate, and expressed similar levels of FABP4, FASN, and PPARG. Differentiation potential was donor dependent, but not precursor cell type dependent. Transcriptomic analysis of differentiated HSCDAs and CMAs from three independent human donors showed that HSCDAs downregulated multiple Hallmark cell cycle pathways relative to CMAs, including E2F Targets, Mitotic Spindle, and G2M Checkpoint. Functional gene set enrichment analysis (fGSEA) confirmed these findings and revealed enrichment of multiple Hallmark transcriptional metabolic pathways in HSCDAs relative to CMAs, including Oxidative Phosphorylation, Adipogenesis, and Fatty Acid Metabolism. We previously reported a tumor study in which we engrafted ID8 Tp53-/- Brca2-/- syngeneic cells by intraperitoneal (IP) injection into mice that were either HSCDA Proficient (HSCDA-Pro; can make both HSCDAs and CMAs) or HSCDA Deficient (HSCDA-Def; can make only CMAs). In that study, we observed reduced IP tumor burden in HSCDA-Def mice relative to HSCDA-Pro mice, including significant reduction of the mass of metastatic tumor nodules within the mesentery. Further analysis revealed lower Ki67 levels in omentum tumor regions in HSCDA-Def mice, suggesting that tumor proliferation was slowed. Transcriptomic analysis of omentum tumors showed that the same three metabolic pathways that were enriched in human HSCDA cultures (Oxidative Phosphorylation, Adipogenesis, and Fatty Acid Metabolism) were depleted in the omentum tumors of HSCDA-Def mice, indicating that ablating HSCDAs altered the tumor metabolic environment. We also found depletion of immune-related Hallmark pathways, indicating that the tumor immune microenvironment was impacted by HSCDA ablation. We examined immune cell infiltration by multispectral immunohistochemistry and found lower densities of dendritic cells (DC) and natural killer cells (NK) in omentum tumors from HSCDA-Def mice than HSCDA-Pro mice. Spatial analysis revealed reduced DCs, NKs, and B-cells in proximity to ID8 tumor cells. We conclude that HSCDAs differentiate similarly to CMAs but are enriched for metabolic pathways that support HGSC progression. Ablation of HSCDAs in mice reduced expression of these pathways, as well as inflammatory pathways and reduced infiltration of specific innate and adaptive immune cell populations. The result of these transcriptional, metabolic, and immune alterations was reduced tumor burden in HSCDA-Def mice. Further studies are underway to examine mechanisms of action and the translational potential of targeting HSCDAs in humans. Citation Format: Francis To, Elizabeth R. Woodruff, Courtney A. Bailey, Timothy M. Sullivan, Joanne K. Maltzahn, Meher P. Boorgula, Vyshnavi Manda, Kathleen M. Gavin, Dwight J. Klemm, Benjamin G. Bitler, Zachary L. Watson. Ablation of hematopoietic stem cell derived adipocytes reduces tumor burden in syngeneic mouse models of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B030.