Stromal metabolism promotes therapeutic resistance in pancreatic cancer

摘要 胰腺导管腺癌（PDA）是一种毁灭性的疾病，五年生存率低于10%。 化疗和免疫疗法的现代进展尚未提供有效的治疗方法。而 Kras的致癌突变在PDA中几乎是普遍的，迄今为止Kras仍然不可治疗。显然，新 需要制定更有效的策略来改善PDA患者的结局。 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。根据该 在此框架下，靶向胰腺肿瘤代谢的几种药物正在临床试验中探索。然而，在这方面， 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，战略 靶向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 与以前的工作一致，我们观察到抑制线粒体代谢是深刻的增长， 对培养的PDA细胞有抑制作用。然而，我们最近发现PDA肿瘤对线粒体有抵抗力- 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抗性。然后我们确定丙酮酸是 在CAF培养基中，在线粒体抑制后恢复PDA细胞增殖的因子。在这项研究计划中， 我们将定义丙酮酸是如何制造和释放的CAFs和如何获得丙酮酸和利用PDA 细胞，以促进对线粒体抑制剂的抗性。我们还将检验丙酮酸释放是 胰腺肿瘤内促进的信号通路参与的CAF特性。这些研究报告将 使用代谢组学技术与代谢和信号传导抑制剂的组合完成 转导同时，我们将在人类患者来源的类器官中破坏这种丙酮酸串扰途径， 模型和原位移植小鼠模型中进行比较，以确定平移值。的应用 这些研究的见解可能会对患者产生直接影响， 正在进行PDA和其他癌症的临床试验。一种预测线粒体活性的方法- 基于肿瘤CAF含量或CAF性质的靶向药物将增加这些药物的效用。

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.