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Principal Investigator: Mandar Deepak Muzumdar
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $62,848
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 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.
Terms: <3-D><3-Dimensional><3D><9-Octadecenoic Acid><Acceleration><Acinar Cell><Aciner Cells><Adipose tissue><Albumins><Award><Binding><Blood Plasma><Body Tissues><Cancer Biology><Cancer Cause><Cancer Etiology><Cancers><Cell Body><Cell Culture System><Cell model><Cells><Cellular Metabolic Process><Cellular model><Cessation of life><Computing Methodologies><Consumption><Country><Cultured Cells><Data><Data Analyses><Data Analysis><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><Grant><Health><High Fat Diet><Histologic><Histologically><Host Factor><Host Factor Protein><Human><In Vitro><Intake><Integration Host Factors><Intermediary Metabolism><Isotopes><KRAS driven oncogenesis><KRAS oncogenesis><KRAS-driven tumorigenesis><KRAS-mediated tumorigenesis><Knock-out><Knockout><Knowledge><Link><Lipase><Lipid Peroxidation><Lipids><Lysophospholipids><MGC14367><MGC15706><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Manuscripts><Membrane><Mentorship><Metabolic><Metabolic Processes><Metabolism><Metaplasia><Metaplastic Change><Methods><Mice><Mice Mammals><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><Pancreas Neoplasms><Pancreas Tumor><Pancreatic><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pancreatic Tumor><Parents><Pathway interactions><Phosphatides><Phospholipids><Plasma><Plasma Serum><Polyunsaturated Fatty Acids><Population><Postdoc><Postdoctoral Fellow><Prevalence><Preventative strategy><Prevention strategy><Preventive strategy><Process><Production><Radioactive><Receptor Protein><Research><Research Associate><Reticuloendothelial System, Serum, Plasma><Risk><Scientist><Side><Source><Supplementation><Survival Rate><Testing><Time><Tissues><Tracer><Training><Triacylglycerol Hydrolase><Triacylglycerol Lipase><Triacylglycerol acylhydrolase><Tributyrinase><Triglyceridase><Triglyceride Lipase><Triolean Hydrolase><Tumor Promotion><United States><Up-Regulation><Upregulation><Variant><Variation><Work><Writing><adipose><adiposity><cancer care><cancer progression><career><cell metabolism><cellular metabaolism><cis-9-Octadecenoic Acid><cohort><computational methodology><computational methods><computer based method><computer methods><computing method><corpulence><data interpretation><developmental><dietary><dietary excess><dietary lipid><diets><driving force><experience><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><mouse model><murine model><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 neoplasia><pancreatic neoplasm><pancreatic oncogenesis><pancreatic tumorigenesis><parent><pathway><pharmacologic><post-doc><post-doctoral><post-doctoral trainee><precancer><precancerous><premalignant><receptor><research associates><skill acquisition><skill development><three dimensional><tributyrase><tumor><tumor progression><tumorigenesis><uptake><white adipose tissue><yellow adipose tissue>