Abstract B069: Bone marrow-derived adipocytes promote ovarian cancer progression and metastasis

Abstract The purpose of this study is to examine the influence of bone marrow-derived adipocytes (BMDAs) on the proliferation and metastasis of high-grade serous carcinoma (HGSC), the most common and aggressive type of ovarian and fallopian tube cancer. BMDAs begin as myeloid cells that traffic to adipose tissue and differentiate into adipocytes. While histologically identical to conventional mesenchymal adipocytes (CMAs), BMDAs are a highly inflammatory subtype. BMDAs accumulate within visceral adipose depots and their production increases with age. BMDA production increases in mouse “pseudomenopause” models (ovariectomy and estrogen receptor alpha knockout), suggesting that BMDAs are likely to extensively accrue in postmenopausal patients. Relative to premenopausal patients, postmenopausal patients have an increased risk of developing HGSC and a two-fold increase in peritoneal metastases at diagnosis. We hypothesize that BMDAs promote HGSC progression and invasion and establish a pro-tumoral niche within peritoneal adipose tissues such as the omentum. We sorted and differentiated primary human adipocyte precursors into BMDAs and CMAs. We examined cytokine secretion in adipocyte conditioned media by multiplex ELISA. We incubated human HGSC cells (PEO1, OVCAR4, and OVCAR8) in conditioned media and assayed proliferation using IncuCyte imaging. We incubated conditioned media on PEO1 ovarian cancer cells and analyzed the cells by reverse phase protein array (RPPA). Finally, we implanted mouse ID8 HGSC cells into syngeneic mice that had been depleted of BMDAs and measured tumor size and metastasis relative to control mice. ELISA showed that BMDA cells secreted elevated amounts of IL-6 and IL-8. In proliferation assays, HGSC cell lines showed increased growth rates in BMDA media. RPPA showed that PEO1 cells incubated in BMDA media upregulated markers of epithelial to mesenchymal plasticity (EMP), as well as pro-survival phosphoprotein signaling (p-AKT1/2). Conversely, PEO1 cells in BMDA media downregulated tumor suppressors protein tyrosine phosphatase non-receptor type 12 (PTPN12), which inhibits proliferation and EMP, and programmed cell death protein 4 (PDCD4), which is pro-apoptotic. Finally, we observed that BMDA depletion in mice reduced primary omentum tumor mass, and also reduced the number and mass of metastatic nodules. In summary, our findings suggest inflammatory signaling from BMDAs promotes HGSC progression and invasion by downregulating HGSC tumor suppressors and subsequent increases in pro-survival and pro-EMP signaling. Further studies are underway to examine the influence of BMDAs on the peritoneal cytokine milieu and the tumor immune microenvironment. Our study may have implications for the development of novel therapeutic and early detection strategies, thereby potentially improving patient outcomes and personalized treatment approaches. Citation Format: Courtney A. Bailey, Elizabeth Woodruff, Joanne Maltzahn, Timothy Sullivan, Ruby Vianzon, Bogdan Conrad, Benjamin G. Bitler, Kathleen Gavin, Dwight Klemm, Zachary L Watson. Bone marrow-derived adipocytes promote ovarian cancer progression and metastasis abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr B069.