Abstract A44: The obesity and pancreatic cancer connection: Crosstalk between adipose, tumor, and stroma

By the year 2030, pancreatic cancer (PC) is projected to be the second deadliest cancer, bypassing breast, prostate, and colorectal cancer-related fatalities. Obesity and a higher BMI (body mass index) have emerged as major risk factors for this deadly disease. Epidemiologic studies indicate that obesity not only increases the risk of developing PC but also promotes tumor aggressiveness and reduces overall patient survival. The mechanism/s by which the obese microenvironment may influence pancreatic tumor progression and aggressiveness are currently unclear. We hypothesize that the increased local presence of mature adipocytes (in obesity) within the pancreatic microenvironment markedly enhances the tumorigenic functions of pancreatic tumors and tumor-associated stroma, thereby promoting PC progression. Mature visceral adipocytes and pancreatic cancer (PC) and pancreatic stellate (PSC) cell lines were used to conduct a variety of in vitro functional assays, including migration, proliferation, gemcitabine chemoresistance, and development of a fibrotic phenotype, to determine whether local interactions between adipocytes and tumor cells promote PC growth and to identify the underlying mechanism/s. Treatment with adipocyte conditioned medium (AdCM) stimulated significantly higher cell migration and invasion rates in PCs (MiaPaca-2, AsPC-1 and BxPC-3) and increased migration in PSCs (HImPSC) compared to serum-free or normal human fibroblast CM. The AdCM-mediated migration was dose dependent and adipocyte specific. AdCM treatment also resulted in a significant increase in proliferation of PCs and PSCs. Given that the development of chemoresistance is a critical challenge in PC therapy, we next investigated the effects of adipocytes on PC cell gemcitabine toxicity. Pretreatment with AdCM resulted in 50-70% increased cell viability for PC and PSCs in the presence of gemcitabine. Since extensive fibrosis is a hallmark of PC, we analyzed the effect of AdCM on excessive ECM production by both PC and PSCs. Compared to cells treated with full medium, AdCM-treated PSC and PC cells significantly upregulated their expression of fibronectin and collagen VI. Phosphoproteome analysis indicated an enrichment of Src family kinases including pSTAT3, pAKT, Hsp90, β-catenin, and Hck in AdCM-treated PCs. Taken together, our results indicate that adipocytes promote cell migration, proliferation, and gemcitabine resistance and induce a fibrotic phenotype in PC and PSC. Current efforts in our laboratory are focused on identifying the adipocyte-secreted factor/s that may mediate these effects. Our findings have the potential to establish a direct causal role for obesity in pancreatic cancer progression as well as to identify relevant pathways in the obesity-pancreatic cancer axis that may be therapeutically targeted in the future. (Supported by The Advanced Medical Research Foundation and The Karp Family Foundation.) Citation Format: Roopali Roy, Takaya Shimura, Adelle Dagher, Marsha A. Moses. The obesity and pancreatic cancer connection: Crosstalk between adipose, tumor, and stroma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A44.