Abstract A090: An inflammatory adipose microenvironment promotes ovarian cancer tumor growth and cisplatin resistance
Authors: Williams Michael E. , Howard David , Gonzalez Deyarina , Taraballi Francesca 
Published: March 2024

Abstract
Epithelial ovarian cancer (EOC) commonly targets the omentum, an adipocyte rich organ of the peritoneum. Omental adipocytes have been shown to promote EOC development and chemoresistance via transfer of free fatty acids (FFAs) and the induction of bi-directional metabolic changes. Furthermore, obesity and adiposity are risk factors for EOC incidence and prognosis. The metastatic peritoneal tumor microenvironment (TME) is highly inflamed, while obesity is often characterized by chronic inflammation of adipose tissue and hyperlipidemia. Given that inflammation of adipocytes is associated with increased release of FFAs, we hypothesized that acute inflammation in the ovarian metastatic TME exacerbates pro-tumorigenic effects of cancer-associated adipocytes. Using a three-dimensional transwell co-culture model, we explore the impact of inflamed adipocytes on EOC activity. Adipocytes generated from human adipose-derived stem cells were inflamed with 100ng/ml TNFα and cultured alongside tumor spheroids generated from EOC cell lines. Cytokine abundance in serum samples from ovarian cancer patients undergoing cisplatin treatment were also analyzed. We found that inflammation of adipocytes increased cellular lipolysis and release of FFAs, as well as inducing de-differentiation and loss of lipid droplets. Upon co-culture with inflamed adipocytes, EOC cells displayed increased proliferation in 2D monolayer and 3D spheroid cultures. Transfer of FFAs from adipocytes to cancer cells was visualized and quantified using a fluorescent fatty acid analog via confocal microscopy and flow cytometry. Co-culture induced expression of fatty acid chaperone protein FABP4 in EOC cell lines, while blocking fatty acid metabolism in cancer cells reversed pro-tumor effects of adipocytes. To understand signaling mechanisms generating bi-directional phenotypic changes, cytokine content of secretome of co-cultures was assessed by Luminex. IL-6 and IL-8 were highly abundant in co-cultures, and increased expression was confirmed by qPCR. Treatment of EOC cell lines with recombinant IL-6 and IL-8 induced increased uptake of FFAs and blocking of IL-6 and IL-8 signaling reversed pro-cancer effects of adipocytes. Serum samples from patients undergoing cisplatin therapy were analyzed and IL-6 and IL-8 levels were found to be associated with resistance to therapy. To further investigate the impact of inflamed adipocyte signaling on therapeutic resistance, co-culture were treated with cisplatin and tumor spheroids were found to be highly resistant in the presence of inflamed adipocytes. STAT3 activity is known to be upregulated by both IL-6 and IL-8 and we found that STAT3 expression was increased in co-cultures. Knockdown of STAT3 in EOC reversed the chemoprotective effects of inflamed adipocytes. These data suggest an important role for inflammation of adipose tissue in the development of therapeutic resistance in EOC and highlight a potential mechanism linking clinically observed associations between obesity and ovarian cancer risk.
Citation Format: Michael E. Williams, David Howard, Deyarina Gonzalez, Francesca Taraballi. An inflammatory adipose microenvironment promotes ovarian cancer tumor growth and cisplatin resistance [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 Suppl_2):Abstract nr A090.