Abstract C081: Opposing effects of white and brown adipose tissue on PDAC growth

Abstract

Abstract The 5-year overall survival for pancreatic ductal adenocarcinoma (PDAC) patients is an abysmal 12% with local disease and 3% for metastatic disease. Obesity is a major risk factor for PDAC showing a three-month decrease in overall survival when compared to lean PDAC patients. The causal relationship between obesity and cancer has driven seminal findings to support a pro-tumorigenic role of white adipose tissue (WAT). Our previous results agreed with wider based studies demonstrating obese WAT as highly inflamed and eliciting pro-tumorigenic effects, through secretion of adipose derived factors that increase tumor proliferation, migration, and xenograft size. While multiple studies have implicated obese WAT as eliciting pro-tumorigenic effects, the effects of brown adipose tissue (BAT) on PDAC have not been explored. Unlike WAT, the BAT is generally protective against obesity, regulates core body temperature, and supports an anti-inflammatory environment. While regulation of these metabolic effects by BAT are well established, the influence of BAT has on PDAC function remains to be determined. Considering its contradictory role to WAT, we hypothesized that BAT would exhibit anti-tumorigenic effects on pancreatic cancer. To test this hypothesis, we isolated and cultured adipose tissue from lean and obese mice in order to collect perigonadal WAT (pgWAT) and BAT conditioned media (CM). PDAC cells were cultured in the absence or presence of pgWAT-CM or BAT-CM and then assayed for alterations in proliferation. While pgWAT induced proliferation of PDAC cells, we detected a significant inhibition of proliferation by BAT-CM. In order to adapt to environmental demands, WAT can convert into BAT and vice versa. Taking account of this phenomenon, we hypothesized that induction of WAT browning would reduce tumor growth by limiting the release of energy-rich molecules from obese WAT and mimicking BAT. To test our hypothesis, 3T3-L1 pre-adipocytes were differentiated into mature white adipocytes and subsequently “browned” by utilizing Cl-316, 243, trametinib, or roscovitine. From these treatments, we validated that brown-like gene signatures were upregulated while white-like gene signatures were downregulated after the treatments. The adipose conditioned media (ACM) from these “browned” adipocytes was applied to a PDAC cell line and proliferation was measured. Our results demonstrated that the browned ACM inhibited PDAC proliferation when compared to non-treated white ACM. These results support the idea that efficient browning of adipose tissue could be therapeutically beneficial for obese PDAC patients. Currently, we are analyzing the ACM from brown adipose tissue and browned WAT to determine alterations in secreted cytokines. Identifying the adipose derived cytokines involved in promoting PDAC proliferation will potentially provide alternate targets for therapeutics. In conclusion, we have identified an anti-tumorigenic role for BAT that further suggests the predominant subtype of adipose is important in relation to PDAC progression. Citation Format: Austin Eades, Michael VanSaun, McKinnon R. Walsh, Bailey Bye, Appolinaire Olou, Joe Ambrose, Jarrid Jack. Opposing effects of white and brown adipose tissue on PDAC growth [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C081.