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Principal Investigator: Gina Lynn Razidlo
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2024
Award: $350,743
Funding agency: National Cancer Institute
Metastasis is the primary cause of cancer death, yet therapeutic strategies to inhibit metastatic invasion do not
exist. The long-term goal of our research program is to define the molecular mechanisms driving metastatic
invasion, with the goal of identifying novel therapeutic targets and strategies to improve cancer survival. While
tumor cells are known to undergo metabolic reprogramming to support tumor growth, the metabolic drivers of
metastasis are poorly understood. This proposed research will define how stored lipids are used as a fuel
source to power metastatic invasion in pancreatic cancer. We have preliminary data that pancreatic tumor cells
undergo a shift towards lipid storage, and that this is required for invasion. This occurs through a suppression
of the hormone sensitive lipase (HSL) by the oncogene KRAS, leading to lipid accumulation and priming tumor
cells for metastasis. These stored lipid droplets are then catabolized during the process of invasion via the
action of lipases. This results in increased oxidative metabolism in the most migratory cells, thereby
coordinating lipid droplet breakdown and fatty acid oxidation with cell migration. These data lead to the
hypothesis for this proposed research that PDAC cells undergo a metabolic shift to favor the accumulation
and storage of lipid droplets, which are catabolized during invasive migration to fuel oxidative phosphorylation
to power metastasis. Using a combination of cell biology, biochemistry, and in vivo models, we will test this
hypothesis by defining the mechanisms of lipase suppression leading to lipid droplet storage (Aim 1), and the
coordinated and localized activation of lipolysis to drive tumor cell invasion (Aim 2). Successful completion of
this research will provide fundamental advances in defining the metabolic pathways regulating invasive
migration, with a focus on lipid droplets, and with the goal of identifying metabolic vulnerabilities in tumor cells
that will provide targets for therapy to block metastasis and improve survival.
Terms: <Acute><Acylcholesterol Lipase><Automobile Driving><Biochemical><Biochemistry><Biological Chemistry><C-K-RAS><Cancer Cause><Cancer Etiology><Cancer Genes><Cancer Treatment><Cancer-Promoting Gene><Cancers><Catabolism><Cell Body><Cell Communication and Signaling><Cell Locomotion><Cell Migration><Cell Movement><Cell Respiration><Cell Signaling><Cells><Cellular Migration><Cellular Motility><Cellular Respiration><Cellular biology><Cessation of life><Cholesterol Ester Hydrolase><Cholesterol Esterase><Cholesteryl Oleate Hydrolase><Cholesterylester Hydrolase><Circulation><Data><Death><Dependence><Disease Progression><Down-Regulation><Energy-Generating Resources><Environment><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Fatty Acids><Genetic Alteration><Genetic Change><Genetic defect><Goals><Hormone-Sensitive Lipase><In Vitro><Intracellular Communication and Signaling><Invaded><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS driven oncogenesis><KRAS oncogenesis><KRAS-driven tumorigenesis><KRAS-mediated tumorigenesis><KRAS2><KRAS2 gene><Ki-RAS><Lead><Lipase><Lipids><Lipoidal Steroid Esterase><Lipolysis><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Mediating><Metabolic><Metabolic Pathway><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Micro-tubule><Microtubules><Mitochondria><Molecular><Mutate><Mutation><Neoplasm Metastasis><Obesity><Oncogene K-Ras><Oncogenes><Outcome><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Pancreas Cancer><Pancreatic Cancer><Pathway interactions><Patients><Pb element><Process><Quantitative Microscopy><RASK2><Regulation><Research><Respiration><Risk Factors><Role><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Source><Steroid Hormone Esterase><Sterol Ester Acylhydrolase><Steryl-ester acylhydrolase><Stimulus><Testing><Therapeutic><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Transforming Genes><Triacylglycerol Hydrolase><Triacylglycerol Lipase><Triacylglycerol acylhydrolase><Tributyrinase><Triglyceridase><Triglyceride Lipase><Triolean Hydrolase><Tumor Cell><Tumor Cell Invasion><Tumor Cell Migration><Tumor Invasion><Tumor Promotion><adiposity><aerobic metabolism><aerobic respiration><anti-cancer therapy><biological signal transduction><cancer cell><cancer cell metabolism><cancer metabolism><cancer metastasis><cancer progression><cancer survival><cancer therapy><cancer-directed therapy><cell biology><cell motility><cholesteryl ester synthase><corpulence><driving><energy source><epigenetically><experiment><experimental research><experimental study><experiments><fat metabolism><fatty acid oxidation><genome mutation><heavy metal Pb><heavy metal lead><improved><in vivo><in vivo Model><insight><lipid metabolism><live cell image><live cell imaging><live cellular image><live cellular imaging><malignancy><migration><mitochondrial><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><oncogenic KRAS><oxidative metabolism><pancreatic cancer cells><pancreatic cancer model><pancreatic malignancy><pancreatic tumor cells><pancreatic tumor model><pathway><programs><respiratory mechanism><social role><spatial integration><sterol esterase><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><trafficking><tributyrase><triterpenol esterase><tumor cell metabolism><tumor cell metastasis><tumor growth><tumor metabolism><tumor progression><uptake><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><virtual>