Stromal metabolism promotes therapeutic resistance in pancreatic cancer

摘要 胰腺导管腺癌(PDA)是一种破坏性疾病，其五年生存率低于10%。 化疗和免疫治疗的现代进展尚未提供有效的治疗方法。而当 Kras的致癌基因突变在PDA中几乎是普遍的，到目前为止，Kras仍然无法用药治疗。显然，这是新的 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为治疗开发提供了有吸引力的靶点。中的单元格 胰腺肿瘤缺乏营养，在低氧环境中持续存在。高肿瘤内压 由癌症相关成纤维细胞(CAF)细胞外基质过度沉积所致 适当的血管形成、营养输送和废物清除。可以预见，PDA细胞劫持了正常的新陈代谢 满足生存和繁殖所需的生物合成和能量需求的途径。根据这一点 在此框架下，几种靶向胰腺肿瘤代谢的药物正在进行临床试验。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，战略 以肿瘤代谢为目标还必须考虑不同类型的细胞在肿瘤中的作用 微环境。 与以前的工作一致，我们观察到线粒体新陈代谢的抑制是深刻的增长 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- 体内靶向治疗。通过一系列生化和代谢组共培养研究，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是单一的 在线粒体抑制后恢复PDA细胞增殖的CAF培养基中的因子。在这项研究提案中， 我们将定义CAF如何制造和释放丙酮酸，以及PDA如何获得和利用丙酮酸 促进细胞对线粒体抑制剂的抵抗力。我们还将测试丙酮酸释放是 一种CAF属性，参与胰腺肿瘤内促进的信号通路。这些研究将是 使用代谢组学技术结合新陈代谢和信号抑制剂完成 转导。同时，我们将在人类患者衍生的有机体中干扰这种丙酮酸串扰途径。 并在小鼠原位移植模型中确定其平移价值。技术的应用 这些研究的见解可能会对患者产生立竿见影的影响，因为线粒体靶向治疗 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属性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.