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.

项目概要激活 KRAS 中的突变可重新编程细胞代谢，以支持生长、增殖和胰腺癌的生存率。然而，关于 KRAS 如何依赖的信息很少新陈代谢的改变有助于癌前状态和癌症的发生。腺泡至导管化生 (ADM) 是胰腺导管中必需的癌前状态腺癌。在 ADM 过程中，腺泡细胞转分化变得更像导管状并且增殖，通常是对组织损伤的反应。 ADM 是可逆的，但会激活突变 KRAS 导致持续性 ADM 并进展为肿瘤和癌症。最近的研究还研究表明，健康的腺泡细胞可以限制和消除致癌的 KRAS 表达细胞。根据初步数据，我假设健康的腺泡细胞在 ADM 有助于氧化还原稳态并限制附近致癌细胞的生长，从而限制癌症的发生。初步实验表明，6-磷酸葡萄糖脱氢酶 (G6pd) 和苹果酸酶 1 (Me1) 转录物显着上调在 ADM 期间。 G6PD 是戊糖磷酸途径中的限速酶，ME1 将苹果酸转化为丙酮酸，连接糖酵解和柠檬酸循环。此外，G6PD 和 ME1 酶产生 NADPH，可防止氧化还原应激。目标 1 将重点关注 G6pd 和 Me1 并确定氧化还原平衡和 NADPH 产生如何促进 ADM 形成。初步实验表明，这些酶的损失增加了腺泡细胞中的活性氧。目标 1 中提出的实验使用基因胰腺癌工程小鼠模型、稳态代谢组学、同位素示踪、和离体原代腺泡细胞培养以检查对 ADM 和肿瘤发生的影响当 G6pd 和 Me1 丢失时，NADPH 池减少。目标 2 将决定如何健康细胞和致癌细胞之间的代谢氧化还原相互作用限制了 ADM。初步的实验表明，健康的腺泡细胞分泌代谢物来抑制邻近的 KRAS- 进行 ADM 的表达细胞。该目标使用 KRAS 驱动的诱导小鼠模型胰腺癌、代谢组学和空间转录组学。拟议的实验将帮助确定健康细胞如何感知邻近致癌细胞的存在以及重新编程它们的细胞状态和新陈代谢以抑制癌症的发生。共同目标该提案中提出的内容将为代谢途径如何发挥作用提供新的机制见解推动胰腺癌的发生，从而为未来的治疗提供信息。