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Principal Investigator: Mandar Deepak Muzumdar
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $183,977
Funding agency: National Cancer Institute
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 this proposal, we aim to test the hypothesis that excess dietary oleic acid directly incorporates into cellular
lipids in the pancreas to drive PDAC development. The studies in Aim 1 utilize sophisticated genetic,
pharmacologic, and dietary approaches to modulate systemic oleic acid levels and establish whether excess
oleic acid is necessary and sufficient to promote pancreatic tumorigenesis. The proposed work in Aim 2 uses
lipidomic analyses to clarify the relationship between dietary fatty acids and pancreatic lipid composition during
PDAC progression and tests whether specific resultant unsaturated lysophospholipids drive tumorigenesis.
Finally, the experiments in Aim 3 combine metabolic and radioactive isotope tracer analyses with conditional
knockout models to decipher the mechanisms by which dietary oleic acid is directly taken up by the pancreas
and whether inhibition of fatty acid uptake pathways in pancreatic cells blocks the pro-tumorigenic effects of oleic
acid. Together, these studies will link fatty acid consumption to specific changes in pancreatic lipid composition
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.
Terms: <3-D><3-Dimensional><3D><9-Octadecenoic Acid><Acceleration><Acinar Cell><Aciner Cells><Adipose tissue><Albumins><Binding><Blood Plasma><Body Tissues><Cancer Cause><Cancer Etiology><Cancers><Cell Body><Cell Culture System><Cell model><Cells><Cellular model><Cessation of life><Consumption><Country><Cultured Cells><Data><Death><Development><Diet><Diet Research><Dietary Fats><Dietary Fatty Acid><Duct><Duct (organ) structure><Ductal Cell><Ductal Epithelial Cell><FASN><FASN gene><Fats><Fatty Acids><Fatty Tissue><Fatty acid glycerol esters><Free Fatty Acids><GEM model><GEMM model><Genes><Genetic><Genetic Models><Genetically Engineered Mouse><Goals><Health><High Fat Diet><Histologic><Histologically><Host Factor><Host Factor Protein><Human><In Vitro><Intake><Integration Host Factors><Isotopes><KRAS driven oncogenesis><KRAS oncogenesis><KRAS-driven tumorigenesis><KRAS-mediated tumorigenesis><Knock-out><Knockout><Link><Lipase><Lipids><Lysophospholipids><MGC14367><MGC15706><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Membrane><Metabolic><Metaplasia><Metaplastic Change><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Monounsaturated Fatty Acids><Murine><Mus><Nonesterified Fatty Acids><OA-519><Obesity><Oleic Acids><Oncogenesis><Organoids><PDA model><PDAC Model><PDAC cancer cell><PDAC cell><Pancreas><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreatic><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pathway interactions><Phosphatides><Phospholipids><Plasma><Plasma Serum><Population><Prevalence><Preventative strategy><Prevention strategy><Preventive strategy><Process><Production><Radioactive><Radioactive Isotopes><Radioisotopes><Radionuclides><Receptor Protein><Reticuloendothelial System, Serum, Plasma><Risk><Side><Source><Supplementation><Survival Rate><Testing><Time><Tissues><Tracer><Triacylglycerol Hydrolase><Triacylglycerol Lipase><Triacylglycerol acylhydrolase><Tributyrinase><Triglyceridase><Triglyceride Lipase><Triolean Hydrolase><United States><Up-Regulation><Upregulation><Variant><Variation><Work><adipose><adiposity><cancer care><cancer progression><cis-9-Octadecenoic Acid><cohort><conditional knock-out><conditional knockout><corpulence><developmental><dietary><dietary approach><dietary excess><dietary lipid><diets><driving force><experiment><experimental research><experimental study><experiments><fat metabolism><feeding><genetically engineered mouse model><genetically engineered murine model><human disease><in vitro Model><in vivo><inhibitor><lipid metabolism><lipidomics><long chain fatty acid><malignancy><membrane structure><neoplasm progression><neoplasm/cancer><neoplastic progression><non-genetic><nongenetic><novel><oncogenic KRAS><pancreatic carcinogenesis><pancreatic ductal adenocarcinoma cell><pancreatic ductal adenocarcinoma model><pancreatic malignancy><pancreatic oncogenesis><pancreatic tumorigenesis><pathway><pharmacologic><precancer><precancerous><premalignant><receptor><three dimensional><tributyrase><tumor><tumor progression><tumorigenesis><tumorigenic><uptake><white adipose tissue><yellow adipose tissue>