LAUSR

Obesity is a major risk factor which drives cancer progression in a variety of cancers, including pancreatic ductal adenocarcinoma (PDAC). In obese individuals the adipose tissue becomes reactive, therefore the crosstalk between adipose tissue and PDAC tumors is essential to understand the mechanisms underlying PDAC progression and cancer associated conditions like cachexia. Lipid loading in pancreatic cancer has been shown to drive a variety of protumor phenotypes, including increased growth and invasiveness. Previous work has shown that cancers including breast, ovarian, and melanoma have the capability to induce lipid transfer from adipocytes to cancer cells. However, lipid transfer from adipocytes to pancreatic cancer cells has not been shown nor has the mechanism been elucidated. In addition, most work has focused on how adipose tissue factors affect the cancer cells, while little has been done to understand how the cancer cells affect the adipocytes. We believe pancreatic cancer cells are capable of inducing lipid release from adipocytes by inducing the destabilization of lipid droplets. To test the capacity of PDAC to induce lipid release and transfer from adipocytes, differentiated adipocytes were loaded with the fatty acid, BODIPY 568 C12, and then co-cultured with pancreatic cancer cells using a transwell coculture system to prevent direct contact. BODIPY labeled lipid uptake was detected in cancer cells using both immunofluorescence microscopy and flow cytometry. In the adipocytes, we observed destabilization of lipid droplet via loss in perilipin 1 immunofluorescence, decreased perilipin levels in western blot analysis, and as a reduction in lipid droplet size after co-culture. Similar results were observed when the experiment was repeated using cancer cell conditioned media instead of a co-culture system. Exposure to cancer conditioned media was found to induce increased pERK in the adipocytes. To determine whether cancer conditioned media was affecting adipocyte mitochondrial function, we used the Agilent Seahorse mitochondrial stress test. Results demonstrated that cancer conditioned media impaired the maximal mitochondrial respiration of adipocytes, which was blocked by MEK inhibition. We conclude that pancreatic cancer cells are capable of inducing lipid transfer from adipocytes by secreting soluble factors which increase lipolysis and MAP kinase signaling in adipocytes. Once lipids have been liberated from the adipocytes, the pancreatic cancer cells scavenge them as an energy source to drive cancer progression. We believe our findings demonstrate an active role for tumor-adipocyte crosstalk and could provide therapeutic targets for the treatment of PDAC in obese individuals or for cancer associated cachexia. Citation Format: Joseph Ambrose, Austin E. Eades, McKinnon Walsh, Michael N. VanSaun. Pancreatic cancer lipid theft is mediated by MAP Kinase signaling in adipocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3168.