University of California, Los Angeles (UCLA)
The roles of free fatty acid receptors (FFARs) and YAP in obesity-promoted pancreatic cancer
Obesity is a known risk factor for the development of pancreatic cancer, a deadly disease for which novel interventions are urgently needed. Free fatty acid receptors (FFARs) 1 and 4, structures on the cell surface that respond to various fatty acids, are novel therapeutic targets for type 2 diabetes, another obesityrelated health issue. However, the roles of these FFARs in cancers are elusive and highly controversial, and have never been explored in obesity-promoted pancreatic cancer. Our pilot data demonstrated that activation of FFAR1 and 4 in pancreatic cancer cells increases the activity of YAP, a cellular molecule promoting tumor growth. Therefore, FFAR1/4 agonists as anti-diabetic therapeutics might raise safety concerns, especially in the obese population with already increased risk of developing pancreatic cancer. Given the great clinical impact, we propose is to elucidate the molecular mechanisms underlying the connection between FFAR1/4 and YAP, and to investigate the biological roles of this crosstalk in the context of obesity-promoted pancreatic cancer. The studies will be carried out using cultured pancreatic cells, as well as clinically relevant spontaneous and transplanted mouse models in which pancreatic tumor development is promoted by a high fat/high calorie diet mimicking the human condition. Insights gained from the proposed research project will be extremely valuable for understanding complex signaling crosstalks in the pathogenesis of pancreatic cancer, which will facilitate the development of novel efficacious interventions. Importantly, it will also provide scientific evidence to guide the appropriate use of novel anti-diabetic therapeutics that are being actively pursued.