Stromal metabolism promotes therapeutic resistance in pancreatic cancer

基质代谢促进胰腺癌的治疗抵抗

基本信息

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
项目类别：
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

项目摘要

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，五年生存率低于 10%。化疗和免疫疗法的现代进步尚未提供有效的治疗方法。尽管 Kras 的致癌突变在 PDA 中几乎普遍存在，迄今为止 Kras 仍然无法成药。显然，新需要制定更有效的策略来改善 PDA 患者的预后。 PDA 细胞利用的代谢途径提供了有吸引力的治疗靶标。细胞在一个胰腺肿瘤营养缺乏，持续存在于缺氧环境中。瘤内压高由癌症相关成纤维细胞（CAF）过度细胞外基质沉积引起的适当的血管化、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。据此框架内，临床试验中正在探索几种针对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。与之前的工作一致，我们观察到线粒体代谢的抑制是深刻的生长对培养中的 PDA 细胞具有抑制作用。然而，我们最近发现 PDA 肿瘤对线粒体具有抗性体内靶向治疗。通过一系列生化和代谢组学共培养研究，我们发现胰腺 CAF 促进对线粒体抑制的抵抗。然后我们确定丙酮酸为单一 CAF 培养基中的因子可在线粒体抑制后恢复 PDA 细胞增殖。在这个研究计划中，我们将定义 CAF 如何产生和释放丙酮酸以及 PDA 如何获取和利用丙酮酸细胞促进对线粒体抑制剂的抵抗。我们还将检验丙酮酸释放是 CAF 特性与胰腺肿瘤内促进的信号通路有关。这些研究将使用代谢组学技术结合代谢和信号抑制剂来完成转导。与此同时，我们将破坏人类患者来源的类器官中的丙酮酸串扰途径模型和原位移植小鼠模型中以确定翻译值。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针对 PDA 和其他癌症进行临床试验。预测线粒体活性的方法基于肿瘤 CAF 含量或 CAF 特性的靶向药物将增加这些药物的效用。