Abstract 5952: Pyroptotic adipocytes contribute to chemoresistance in advanced stage ovarian cancer
Authors: Lin Chang-Ni , Liang Yu-Ling , Hsu Keng-Fu , Wu Yi-Ying 
Published: April 2023

Background: Ovarian cancer is known the gynecologic malignancy with the highest case-to-fatality ratio. Once appear metastasis, the 5 years survival rate reduce to 30-40% in these patients. Different with hematogenously metastasizing tumors, ovarian cancer cells primarily disseminate within the peritoneal cavity. Omentum, a lipid-rich tissue, is the most common metastatic site of ovarian cancer. In addition, the adipocyte-released free fatty acid can be used by cancer cells to fuel its growth and proliferation. In this study, we attempt to clarify the regulation between metastatic ovarian cancer cell and omental adipocytes, and find a therapeutic strategy for advanced stage ovarian cancer.

Materials and Methods: A three-cell (SKOV3, 3T3L1 and THP-1) co-culture model was established to mimic in vitro tumor microenvironment of ovarian cancer omental metastasis. Flow cytometry was performed for the adipocytes survival rate with Annexin V/PI double staining. Caspase-1 activity assay was used to detect the cleavage of substrate YVAD-AFC level in adipocytes and quantified by a fluorescence microliter plate reader. The free fatty acid assay kit was used to detect free fatty acid level in condition medium and ascites. Invasion assay and MTT assay were used to validate the invasive ability and cell viability of ovarian cancer cells. Immunohistochemistry was used to CD36 staining in clinical specimens, and correlation analysis through prism 8 software. Results: We observed the adipocyte pyroptosis in 3-cell co-culture model, and the free fatty acid increased in culture medium by flow cytometry analysis, caspase-1 activity assay kit and free fatty acid assay kit. In the meantime, the invasive ability and cisplatin resistance increased in ovarian cancer cells. The free fatty acid level in ascites positive correlated with CD36 expression (r2=0.2189, p=0.0375). Of note, combination treatment of cisplatin and sulfosuccinimidyl oleate (SSO) can reverse chemoresistance in 3-cell co-culture model. Overall, free fatty acid released form the pyroptotic adipocytes and increase invasive ability and chemoresistance in ovarian cancer cells. Block the interaction of free fatty acid and CD36 can reverse the chemoresistance in advanced ovarian cancer.

Conclusion: In this study, we demonstrated adipocytes pyroptosis can increase the free fatty acid release to the microenvironment, and then promote ovarian cancer cell invasion and increase chemoresistance. For more important, inhibition of free fatty acid and CD36 interaction can reverse the chemoresistance in the in vitro experiments. Thus, reduce the adipocytes pyroptosis may be a novel therapeutic strategy for the omentum metastatic ovarian cancer.

Citation Format: Chang-Ni Lin, Yu-Ling Liang, Keng-Fu Hsu, Yi-Ying Wu. Pyroptotic adipocytes contribute to chemoresistance in advanced stage ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5952.