Dietary fatty acids drive pancreatic cancer development

PROJECT SUMMARY/ABSTRACT Despite significant advances in cancer care, pancreatic ductal adenocarcinoma (PDAC) remains the third leading cause of cancer death in the United States with a 5-year survival rate of ~10%. Obesity and high fat diet (HFD) consumption increase PDAC risk in human cohorts and accelerate PDAC progression in mice, but the

mechanistic basis for these relationships is not well understood. Given the rapid rise in both the worldwide prevalence of obesity and consumption of dietary fat, deciphering mechanisms of obesity-driven PDAC could broadly impact human health. The translational relevance of prior diet research, however, has been limited by

uncontrolled variations in fat source and intake across human populations and mouse experiments. Therefore, whether and how specific dietary fats promote pancreatic tumorigenesis remain critical unanswered questions of great societal importance. Leveraging a unique isocaloric panel of HFDs differing only in fat source, we

identified a correlation between consumption of diets high in oleic acid – a monounsaturated fatty acid typically associated with good health – and enhanced tumor development in a genetic model of PDAC that faithfully mimics the genetic and histologic progression of the human disease. We further observed that tumorigenesis

correlated with increased incorporation of oleic acid into specific phospholipids in tissues, including the pancreas. In the parent R01 proposal, we aim to test the hypothesis that excess dietary oleic acid directly incorporates into cellular lipids in the pancreas to drive PDAC development. Specifically, we seek to: 1) to establish whether

excess oleic acid is necessary and sufficient to promote pancreatic tumorigenesis; 2) to clarify the relationship between dietary fatty acids and pancreatic lipid composition; and 3) to decipher the mechanisms by which dietary oleic acid is directly taken up by the pancreas. Based on preliminary studies from the parent R01, we focus this

supplement on determining the downstream mechanisms by which dietary fatty acids alter cellular metabolism to promote tumor formation in the pancreas. We aim: 1) to investigate how dietary modulation of pancreatic phospholipid species perturbs lipid peroxidation and ferroptosis sensitivity in early pancreatic tumorigenesis; and

2) to determine whether excess dietary polyunsaturated fatty acids suppress pancreatic tumor progression. The supplement will support a promising associate research scientist, enabling him to pursue these aims, acquire additional mentorship and training in cancer biology, mouse models, lipidomics, data analysis (including

computational methods), and manuscript and grant writing. These experiences will allow him to acquire the skills and knowledge he needs to develop an independent research career. Together, these studies will link fatty acid consumption to specific changes in pancreatic cell metabolism as driving forces in PDAC progression. Results

from this work have transformative potential to identify novel targeted dietary and pharmacologic strategies for the prevention of a largely incurable cancer.