Document text
Principal Investigator: Megan DeAnna Radyk
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $125,000
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
Acinar-to-ductal metaplasia (ADM) is a regenerative state that leads to repair of the pancreas
after injury. During ADM, acinar cells transdifferentiate to a duct-like cell and become
proliferative. ADM is typically reversible; however, ADM is also a risk factor for the development
of pancreatic ductal adenocarcinoma. Activating mutations in KRAS lead to persistent ADM and
progression to pancreatic intraepithelial neoplasia (PanIN) and cancer. Many studies describe
how cell metabolism is reprogrammed in cancer, though little is known about the role of
metabolism in regulating precancerous stages, like ADM and PanIN. I hypothesize that 1. cell
metabolism is altered in ADM to upregulate redox homeostasis, and 2. healthy acinar cells
maintain a metabolic microenvironment that is restrictive for ADM and PanIN progression.
Previous work shows that genes for NADPH-producing enzymes, Glucose-6-phosphate
dehydrogenase (G6pd) and Malic enzyme 1 (Me1) are upregulated during ADM to maintain
redox homeostasis and glutathione recycling. Preliminary also suggest that glutathione
biosynthesis pathways are necessary for controlled ADM development. Aim 1 will
mechanistically focus on Me1 and determine how Me1-loss contributes to ADM and PanIN
formation. The experiments proposed in Aim 1 use genetically engineered mouse models of
pancreatic cancer, steady-state metabolomics, isotope tracing, and ex vivo primary acinar cell
culture. Aim 2 will address if altered glutathione biosynthesis promotes ADM formation. It will
interrogate if blocking cystine import (via loss of a subunit of the system xC– antiporter) and a
rate-limiting enzyme in glutathione synthesis increases reactive oxygen species in the cell and
promotes ADM. Aim 3 (R00 focus) will determine if healthy acinar cells contribute to a restrictive
environment for the development of ADM and PanIN, even when oncogenic Kras is present.
Preliminary experiments suggest that healthy acinar cells secrete metabolites to inhibit adjacent
cells from undergoing ADM. Pilot spatial transcriptomic experiments have also identified
potential metabolic genes important for ADM restriction. This aim uses inducible mouse models
of Kras-driven pancreatic cancer, metabolomics, and spatial transcriptomics. Together, the aims
presented in this proposal will provide new mechanistic insights on how metabolic pathways
control the formation of precancerous states in the pancreas.
Terms: <Acceleration><Acinar Cell><Aciner Cells><Active Oxygen><Address><Anabolism><Antioxidants><Autoregulation><Biomass><Body Tissues><Buffers><C-K-RAS><Cancer Cause><Cancer Etiology><Cancer Genes><Cancer-Promoting Gene><Cancers><Cell Body><Cell Culture Techniques><Cell secretion><Cells><Cellular Metabolic Process><Cellular Secretion><Cessation of life><Co-culture><Cocultivation><Coculture><Coculture Techniques><Coenzyme II><Communication><Complex><Critical Paths><Critical Pathways><Cystine><D-Galactoside-Binding Lectin><Data><Death><Detection><Development><Duct><Duct (organ) structure><EC 1.1.1.49><Early Diagnosis><Environment><Enzyme Gene><Enzymes><G6PD><G6PD deficiency><G6PD gene><G6PD1><GEM model><GEMM model><GPD Deficiency><GSSG><Galactose Binding Lectin><Galaptins><Galectins><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetically Engineered Mouse><Gln><Glucose-6-Phosphate Dehydrogenase><Glucosephosphate Dehydrogenase><Glucosephosphate Dehydrogenase Deficiency><Glutamine><Glutathione><Glutathione Disulfide><Grant><Growth><Homeostasis><Human><Injury><Intermediary Metabolism><Isotopes><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><K-ras mouse model><KRAS><KRAS driven oncogenesis><KRAS oncogenesis><KRAS(G12D)><KRAS-driven tumorigenesis><KRAS-mediated tumorigenesis><KRAS2><KRAS2 gene><KRASG12D><Ki-RAS><Kras mouse model><Kras murine model><L-Cystine><L-Glutamine><Lead><Lesion><LoxP-flanked allele><Malates><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Measures><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Metaplasia><Metaplastic Change><Mice><Mice Mammals><Modeling><Modern Man><Mouse Strains><Murine><Mus><Mutation><NAD phosphate><NAD(H) phosphate><NADH phosphate><NADP><NADPH><Nicotinamide-Adenine Dinucleotide Phosphate><Oncogene K-Ras><Oncogenes><Oncogenesis><Oncogenic><Organ><Oxidation-Reduction><Oxidized Glutathione><Oxygen Radicals><PanIN><Pancreas><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreas Neoplasms><Pancreas Tumor><Pancreatic><Pancreatic Cancer><Pancreatic Diseases><Pancreatic Disorder><Pancreatic Duct Dysplasia><Pancreatic Ductal Adenocarcinoma><Pancreatic Ductal Dysplasia><Pancreatic Intraepithelial Neoplasia><Pancreatic Tumor><Pathway interactions><Pb element><Physiological Homeostasis><Precancerous Conditions><Premalignant Condition><Premalignant State><Pro-Oxidants><Process><Production><Proliferating><Pyruvate><Q Levoglutamide><Q. Levoglutamide><RASK2><RNA Seq><RNA sequencing><RNAseq><Reactive Oxygen Species><Recycling><Redox><Reduced Glutathione><Regulation><Repression><Risk Factors><Role><S-Type Lectins><Supporting Cell><Survival Rate><System><Testing><Therapeutic><Tissue Growth><Tissues><Transforming Genes><Triphosphopyridine Nucleotide><Work><antiporter><beta-D-Galactosyl-Specific Lectin><beta-Galactoside Binding Lectin><biobank><biorepository><biosynthesis><cancer initiation><cancer progression><cell culture><cell cultures><cell metabolism><cell type><cellular metabaolism><cofactor><developmental><driver lesion><driver mutation><early detection><effective therapy><effective treatment><experiment><experimental research><experimental study><experiments><floxed><floxed allele><gamma-L-Glu-L-Cys-Gly><gamma-L-Glutamyl-L-Cysteinylglycine><genetically engineered mouse model><genetically engineered murine model><genome mutation><glucose 6 phosphate dehydrogenase deficiency><heavy metal Pb><heavy metal lead><in vivo><injured><injuries><innovate><innovation><innovative><insight><malic enzyme><malignancy><metabolism measurement><metabolomics><metabonomics><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic progression><novel><oncogenic KRAS><ontogeny><oxidation reduction reaction><pancreas development><pancreas disorder><pancreas duct dysplasia><pancreas ductal dysplasia><pancreatic cancer model><pancreatic carcinogenesis><pancreatic malignancy><pancreatic metaplasia><pancreatic neoplasia><pancreatic neoplasm><pancreatic oncogenesis><pancreatic tumor model><pancreatic tumorigenesis><pathway><pharmacologic><precancer><precancerous><precancerous state><premalignant><pyruvic-malic carboxylase><regenerative><repair><repaired><social role><transcriptome sequencing><transcriptomic sequencing><transcriptomics><transdifferentiation><tumor><tumor progression><tumorigenesis><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog>