Investigating Mechanisms Of Obesity-Mediated Pancreatic Cancer Progression.

Genetically engineered mouse models (GEMMs) that faithfully recapitulate the genetics and histology of human tumors are an underutilized tool to understand how modifiable risk factors influence tumor development. Prospective cohort studies have shown that obesity is associated with an increased risk of developing pancreatic cancer, more advanced disease at diagnosis, and worse survival, though the precise mechanisms behind which obesity contributes to cancer progression remain elusive. We crossed mice harboring loss-of-function mutations in the leptin gene ( ob/ob ) with Pdx1-Cre; LSL-Kras G12D ( KC ) mice predisposed to initiate pancreatic cancers. KC; ob/ob mice are obese and exhibit markedly shortened survival (~4 months vs. ~1 year), increased primary tumor burden, and enhanced progression to adenocarcinoma compared to nonobese KC mice. Interestingly, early correction of leptin deficiency using an adeno-associated virus (AAV)-based approach induces rapid normalization of body weight and hyperglycemia and completely prevents the emergence of enhanced tumor burden. In contrast, late leptin restoration following tumor progression does not impact survival. These data suggest a causal and reversible role for obesity in early pancreatic cancer progression. Furthermore, by evaluating the degree by which alternative interventions phenocopy the effects of leptin restoration, we have developed a model to rapidly interrogate mechanisms of obesity-mediated tumor progression. As a proof of principle, we have tested the ability of immunomodulatory (aspirin) and antidiabetic (metformin) agents, observed to impact pancreatic cancer risk and survival in human cohorts, to intercept cancer progression in this model. Finally, combined molecular and biochemical analyses of tumors reveal increased immune cell activation and fibrosis in KC; ob/ob mice compared to nonobese KC and KC; p53 mutant mice and provide specific molecular targets to evaluate for pancreatic cancer therapy and prevention. Citation Format: Mandar Deepak Muzumdar, Kimberly Judith Dorans, Katherine Minjee Chung, Arjun Bhutkar, Charles Fuchs, Tyler Jacks. Investigating mechanisms of obesity-mediated pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A05.