Stromal metabolism promotes therapeutic resistance in pancreatic cancer

基质代谢促进胰腺癌的治疗抵抗

• 批准号: 10368125
• 负责人: Costas Andreas Lyssiotis
• 金额: $ 40.12万
• 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: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10368125
• 关键词: Alleles; Anabolism; Biochemical; Blood Vessels; Cell Proliferation; Cells; Chemotherapy and/or radiation; Clinical Trials; Coculture Techniques; Communication; Deposition; Desmoplastic; Disease; Environment; Excision; Extracellular Matrix; Fibroblasts; Generations; Genetic; Genetically Engineered Mouse; Goals; Growth; Homeostasis; Human; Hypoxia; Immunocompetent; Immunotherapy; Impairment; In Vitro; Isotopes; KRASG12D; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial Aspartate Aminotransferase; Modeling; Modernization; Mutation; NADH; NADH oxidase; Neoplasm Transplantation; Non-Malignant; Nutrient; Oncogenic; Organelles; Organoids; Oxidation-Reduction; Oxygen; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Proliferating; Property; Pyruvate; Pyruvate Metabolism Pathway; Reaction; Reporting; Research Proposals; Resistance; Role; Scheme; Series; Signal Pathway; Signal Transduction; Stromal Cells; Survival Rate; System; Techniques; Testing; Therapeutic; Translations; Transplantation; Treatment Efficacy; Vascularization; Work; Xenograft procedure; base; cancer cell; cancer therapy; cancer type; cell growth; cell type; chemotherapy; clinical application; density; effective therapy; efficacy evaluation; human model; improved outcome; in vivo; inhibitor; insight; interest; metabolomics; mitochondrial metabolism; mouse model; novel; oxidation; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pressure; prevent; targeted agent; targeted treatment; therapy resistant; treatment strategy; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor xenograft; wasting

ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is a devastating disease with a five-year survival rate below 10%. 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 for patients with PDA. 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. According to this framework, several agents that target pancreatic tumor metabolism are being explored in clinical trials. However, PDA cells also support their metabolic demands via interaction with non-malignant cells. Thus, strategies targeting tumor metabolism must also take into consideration the role of the diverse cell types in the tumor microenvironment. Consistent with previous work, we observed that inhibition of mitochondrial metabolism is profoundly growth inhibitory to PDA cells in culture. Yet, we more recently found that PDA tumors are resistant to mitochondrial- targeted therapies in vivo. Through a series of biochemical and metabolomic co-culture studies, we found that pancreatic CAFs promotes resistance to mitochondrial inhibition. We then identified pyruvate as the single factor in CAF media that restored PDA cell proliferation upon mitochondrial inhibition. In this research proposal, we will define how pyruvate is made and released by CAFs and how pyruvate is obtained and utilized by PDA cells to promote resistance to mitochondrial inhibitors. We will also test the hypothesis that pyruvate release is a CAF property engaged by signaling pathways promoted within pancreatic tumors. These studies will be accomplished using metabolomics techniques in combination with inhibitors of metabolism and signal transduction. In parallel, we will disrupt this pyruvate crosstalk pathway in human patient-derived organoid models and in orthotopic transplant mouse models to determine the translation value. The application of insights from these studies could have an immediate impact on patients, as mitochondrially-targeted therapies are being tested in clinical trials for PDA and other cancers. A means to predict activity of mitochondrially- targeted agents based on tumor CAF content or CAF properties would increase the utility of these agents.

抽象的 胰腺导管腺癌（PDA）是一种毁灭性疾病，生存率低于10％。 化学疗法和免疫疗法的现代进步尚未提供有效的疗法。尽管 KRAS中的致癌突变在PDA中几乎是普遍的，迄今为止，KRAS仍然不可能。显然，新的 需要采取策略来制定更有效的策略，以改善PDA患者的预后。 PDA细胞使用的代谢途径提出了有吸引力的靶标，以利用治疗方法。细胞中的细胞 胰腺肿瘤是养分贫困的，在低氧环境中持续存在。高肿瘤内压力 由癌症相关的成纤维细胞（CAF）的细胞外基质沉积过多引起 适当的血管化，养分输送和清除废物。可以预见的是，PDA细胞劫持正常代谢 满足生存和增殖所需的生物合成和能量需求的途径。据此 在临床试验中，正在探索靶向胰腺肿瘤代谢的几种靶向胰腺肿瘤代谢的药物。然而， PDA细胞还通过与非恶性细胞的相互作用来支持其代谢需求。因此，策略 靶向肿瘤代谢还必须考虑到各种细胞类型在肿瘤中的作用 微环境。 与以前的工作一致，我们观察到抑制线粒体代谢是深刻的生长 对培养物中PDA细胞的抑制作用。但是，我们最近发现，PDA肿瘤对线粒体具有抗性 靶向疗法在体内。通过一系列生化和代谢组培养研究，我们发现 胰腺CAF促进了对线粒体抑制的抗性。然后，我们将丙酮酸识别为单个 在线粒体抑制后恢复PDA细胞增殖的CAF培养基中的因子。在这项研究建议中， 我们将定义如何由CAFS制造和释放丙酮酸以及如何通过PDA获得和利用丙酮酸 细胞促进对线粒体抑制剂的抗性。我们还将测试丙酮酸释放的假设 在胰腺肿瘤中促进的信号通路参与的CAF特性。这些研究将是 使用代谢组学技术与代谢和信号抑制剂结合完成 转导。同时，我们将破坏人类患者衍生的类器官中的这种丙酮酸串扰途径 模型和原位移植小鼠模型以确定翻译值。应用 这些研究的见解可能会对患者产生直接影响，因为线粒体靶向疗法 正在对PDA和其他癌症的临床试验进行测试。一种预测线粒体活性的手段 基于肿瘤CAF含量或CAF特性的靶向药物会增加这些药物的效用。