Metabolic interactions in the pancreatic tumor microenvironment

胰腺肿瘤微环境中的代谢相互作用

• 批准号: 9911388
• 负责人: Samuel Andrew Kerk
• 金额: $ 3.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911388
• 关键词: Adenocarcinoma Cell; Cells; Data; Defect; Deposition; Desmoplastic; Digit structure; Drug Delivery Systems; Environment; Enzymes; Equilibrium; Excision; Extracellular Matrix; Fibroblasts; Glucose; Glycolysis; Goals; Growth; Homeostasis; Hypoxia; Immunosuppression; Immunotherapy; Impairment; In Vitro; Isotopes; Label; Laboratories; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial Aspartate Aminotransferase; Modeling; Modernization; Mutation; Natural regeneration; Nutrient; Oncogenic; Operative Surgical Procedures; Oxidation-Reduction; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phenocopy; Phenotype; Play; Proliferating; Property; Pyruvate; Resistance; Respiration; Role; Stress; Stromal Cells; Supplementation; Supporting Cell; Survival Rate; Testing; Therapeutic; Treatment Efficacy; Vascularization; Veins; Work; anticancer research; base; cancer cell; cancer therapy; cancer type; cell growth; cell type; chemotherapy; effective therapy; improved outcome; in vivo; inhibitor/antagonist; knock-down; mitochondrial metabolism; mouse model; mutant; neoplastic cell; novel therapeutic intervention; pancreatic cancer cells; pancreatic cancer model; pancreatic neoplasm; pre-clinical; pressure; prevent; therapy resistant; tumor; tumor growth; tumor metabolism; tumor microenvironment; uptake; wasting

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a deadly form of cancer with few treatment options available to patients. Modern advances in chemotherapy and immunotherapy have yet to provide effective treatments. While oncogenic mutations in Kras are nearly universal in PDA, to date Kras remains undruggable. Clearly, new strategies are needed to develop more effective strategies to improve outcomes in PDA. The metabolic pathways utilized by PDA cells present attractive targets to exploit therapeutically. The cells in a pancreatic tumor are nutrient-deprived and persist in a hypoxic environment. High intratumoral pressure caused by excessive extracellular matrix deposition from the cancer-associated fibroblasts (CAFs) prevents proper vascularization, nutrient delivery, and waste removal. Predictably, PDA cells hijack normal metabolic pathways to meet the biosynthetic and energetic demands required to survive and proliferate. In addition, cancer cells also utilize non-cell autonomous pathways to meet metabolic demands. Thus, strategies targeting tumor metabolism must also take into consideration the role of the diverse cell types in the tumor microenvironment. Previous work in my lab revealed that PDA cells utilize glutamate oxaloacetate transaminase 2 (GOT2) to protect against stress and support proliferation. Despite this profound growth inhibitory effect in vitro, I found that GOT2 knockdown (KD) PDA tumors were able to grow in vivo. My preliminary data indicate that culturing PDA GOT2KD cells in media conditioned by cancer-associated fibroblasts (CAFs), which are highly prevalent in an in vivo pancreatic tumor, restores proliferation in vitro. I then identified pyruvate as the single factor in CAF media that restored growth upon GOT2 knockdown and protected PDA cells from mitochondrial inhibitors. The working hypothesis of this proposal is that CAFs support PDA metabolism when redox homeostasis and mitochondrial respiration are disrupted. This hypothesis will be tested in two aims. In Aim 1, I will seek to discover how CAFs are producing and releasing pyruvate. Aim 2 will elucidate the mechanism by which pyruvate supports PDA growth during mitochondrial inhibition. Further, I will test the role of this pathway in PDA tumor growth using preclinical mouse models of pancreatic cancer to determine the therapeutic utility of targeting mitochondrial metabolism and pyruvate-releasing CAFs in PDA.

项目摘要 胰腺导管腺癌（PDA）是一种致命的癌症， 患者化疗和免疫疗法的现代进展尚未提供有效的治疗方法。 虽然Kras的致癌突变在PDA中几乎是普遍的，但迄今为止Kras仍然不可治疗。很显然， 需要新的策略来开发更有效的策略以改善PDA的结果。 PDA细胞利用的代谢途径提供了有吸引力的治疗靶点。中的细胞 胰腺肿瘤缺乏营养并在缺氧环境中持续存在。高瘤内压 由癌症相关成纤维细胞（CAF）的过量细胞外基质沉积引起， 适当的血管化、营养输送和废物清除。可以预见的是，PDA细胞劫持了正常的代谢 这是满足生存和增殖所需的生物合成和能量需求的途径。此外，本发明还提供了一种方法， 癌细胞还利用非细胞自主途径来满足代谢需求。因此，针对 肿瘤代谢还必须考虑到肿瘤中不同细胞类型的作用 微环境 我实验室以前的工作表明，PDA细胞利用谷氨酸草酰乙酸转氨酶2（GOT2）， 防止压力和支持扩散。尽管在体外有这种深刻的生长抑制作用，我发现 GOT2敲低（KD）PDA肿瘤能够在体内生长。我的初步数据显示， PDA GOT2KD细胞在由癌症相关成纤维细胞（CAF）调节的培养基中， 在体内胰腺肿瘤中，在体外恢复增殖。然后我确定丙酮酸是 CAF培养基在GOT2敲低后恢复生长并保护PDA细胞免受线粒体抑制剂的影响。 该建议的工作假设是，CAF在氧化还原稳态时支持PDA代谢， 线粒体呼吸被破坏。这一假设将在两个目标中得到检验。在目标1中，我将寻求 发现CAFs如何产生和释放丙酮酸。目标2将阐明 丙酮酸在线粒体抑制期间支持PDA生长。此外，我将测试这条途径在以下方面的作用： 使用胰腺癌的临床前小鼠模型测定PDA肿瘤生长以确定 靶向PDA中的线粒体代谢和释放腺苷酸的CAF。