Deciphering the Mechanistic Link between Obesity and Pancreatic Cancer

Epidemiologic studies in prospective human cohorts have confirmed an association between obesity and an increased risk of developing over a dozen types of cancer, including pancreatic cancer. Yet, the precise mechanisms by which obesity drives tumor progression remain elusive and represent a major untapped target to develop novel strategies for cancer prevention and therapy.

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. We have developed a GEMM of obesity-associated pancreatic cancer demonstrating a causal and reversible role for obesity in early pancreatic cancer development, wherein obesity accelerates tumor progression while weight loss impedes it. Leveraging this model, we have identified a previously unappreciated endocrine-exocrine signaling axis, distinct from insulin, which drives pancreatic tumorigenesis. Ongoing molecular and biochemical analyses of tumors from these mice are revealing additional molecular targets and pathways by which obesity promotes tumorigenesis.