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

• 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
• 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

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.

项目摘要 激活KRAS重新编程细胞代谢中的突变，以支持生长，增殖和 胰腺癌的生存。但是，关于如何依赖Kras的信息很少 新陈代谢的改变有助于抗癌症和癌症的启动。 ac 导管化生（ADM）是胰腺导管中必不可少的癌前状态 腺癌。在ADM期间，腺泡细胞转化会变得更类似管状，并且 加剧性，通常是针对组织损伤的。 ADM是可逆的，但激活了突变 KRAS导致ADM持续发展，并发展为肿瘤和癌症。最近的研究 表明健康的腺泡细胞可以限制并消除表达致癌KRAS的细胞。 根据初步数据，我假设健康的腺泡细胞改变了其新陈代谢 ADM有助于氧化还原稳态并限制附近的致癌细胞的生长，从而 限制癌症的开始。初步实验表明葡萄糖6-磷酸盐 脱氢酶（G6PD）和MALIC酶1（ME1）转录本显着上调 在ADM期间。 G6PD是五磷酸五磷酸途径和ME1中限制酶的速率 将苹果酸转化为丙酮酸，将糖酵解和柠檬酸周期连接起来。此外，G6PD和 ME1酶产生NADPH，可防止氧化还原胁迫。 AIM 1将专注于G6PD 和ME1，并确定氧化还原平衡和NADPH生产如何为ADM做出贡献 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。 AIM 1中提出的实验在遗传上使用 胰腺癌的工程小鼠模型，稳态代谢组学，同位素跟踪， 和离体原发性腺泡细胞培养物，以检查对ADM和肿瘤发生的后果 当G6PD和ME1丢失时，NADPH池减少。 AIM 2将决定如何 健康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抑制相邻的kras- 表达来自ADM的细胞。此目的使用KRAS驱动的诱导鼠标模型 胰腺癌，代谢组学和空间转录组学。提出的实验将 帮助确定健康​​细胞如何感知邻近的致癌细胞的存在和 重新编程其细胞状态和代谢以抑制癌症的起步。在一起，目的 在本提案中提出的将提供有关代谢途径的新机械见解 驱动胰腺癌的启动，从而告知未来的治疗剂。