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Metabolic pathways regulate metaplasia and cancer initiation in the pancreas

代谢途径调节胰腺化生和癌症发生

基本信息

批准号：
10675815
负责人：
Megan DeAnna Radyk
金额：
$ 6.95万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10675815
关键词：
Acinar Cell Antioxidants Biomass Buffers Cancer Etiology Cell Culture Techniques Cell Survival Cell secretion Cells Cellular Metabolic Process Cessation of life Citric Acid Cycle Coculture Techniques Communication Critical Pathways Cytoprotection Data Detection Development Disease Progression Duct (organ) structure Ensure Environment Enzymes Equilibrium Future G6PD gene Gene Expression Genes Genetic Genetically Engineered Mouse Glucosephosphate Dehydrogenase Glutamine Glutathione Growth Homeostasis Human Immunologic Surveillance Injury Isotopes K-ras mouse model KRAS oncogenesis KRAS2 gene Lead Lesion Link Literature Malates Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Metabolic Pathway Metabolism Metaplasia Metaplastic Cell Mouse Strains Mus Mutation NADP Neoplasms Normal Cell Oncogenes Oncogenic Organ Oxidation-Reduction Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pathway interactions Pentosephosphate Pathway Phenotype Pilot Projects Precancerous Conditions Process Production Proliferating Pyruvate Reactive Oxygen Species Reduced Glutathione Repression Research Proposals Role Route Source Stress Survival Rate System Therapeutic Tissues Transcript United States Work cancer initiation cell type cofactor driver mutation experimental study human disease human tissue in vivo innovation insight malic enzyme metabolomics mouse model mutant new therapeutic target novel novel diagnostics pancreatic cancer model pancreatic neoplasm pre-clinical premalignant programs response transcriptome sequencing transcriptomics transdifferentiation tumor tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Activating mutations in KRAS reprogram cell metabolism to support growth, proliferation, and survival in pancreatic cancer. However, there is little information on how KRAS-dependent alterations in metabolism contribute to premalignant states and cancer initiation. Acinar-to- ductal metaplasia (ADM) is a precancerous state essential in pancreatic ductal adenocarcinoma. During ADM, acinar cells transdifferentiate to become more duct-like and proliferative, usually in response to tissue damage. ADM is reversible but activating mutations in KRAS lead to persistent ADM and progression to neoplasia and cancer. Recent studies also show that healthy acinar cells can restrict and eliminate oncogenic KRAS-expressing cells. Based on preliminary data, I hypothesize that healthy acinar cells alter their metabolism during ADM to aid in redox homeostasis and restrict the growth of nearby oncogenic cells, thereby restricting cancer initiation. Preliminary experiments show that Glucose-6-phosphate dehydrogenase (G6pd) and Malic enzyme 1 (Me1) transcripts are significantly upregulated during ADM. G6PD is the rate limiting enzyme in the pentose phosphate pathway and ME1 converts malate to pyruvate, linking glycolytic and citric acid cycles. In addition, both G6PD and ME1 enzymes produce NADPH, which protects against redox stress. Aim 1 will focus on G6pd and Me1 and determine how redox balance and NADPH production contribute to ADM formation. Preliminary experiments show that loss of these enzymes increased the level of reactive oxygen species in acinar cells. 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 to examine the consequence on ADM and tumorigenesis when G6pd and Me1 are lost, and NADPH pools are reduced. Aim 2 will determine how metabolic redox interactions between healthy and oncogenic cells restrict ADM. Preliminary experiments suggest that healthy acinar cells secrete metabolites to inhibit adjacent KRAS- expressing cells from undergoing ADM. This aim uses inducible mouse models of KRAS-driven pancreatic cancer, metabolomics, and spatial transcriptomics. The proposed experiments will help to identify how healthy cells sense the presence of neighboring oncogenic cells and reprogram their cell state and metabolism to repress cancer initiation. Together, the aims presented in this proposal will provide new mechanistic insights on how metabolic pathways drive pancreatic cancer initiation, thereby informing future therapeutics.

项目总结