Understanding cell intrinsic and context dependent metabolic adaptations of cancer cell

项目摘要/摘要 癌细胞的特征是异常增殖和新陈代谢改变。为了增殖，肿瘤细胞必须 调整它们的新陈代谢，以获得核苷酸、蛋白质和脂类，以支持生长和分裂。虽然 在所有癌细胞中观察到满足这些生物合成需求的代谢改变，代谢需求如何 以及这是否会影响癌细胞在不同组织中的增殖能力 转移的部位还不是很清楚。这一点尤其重要，因为转移性癌症更难 治疗效果优于原发癌症，而组织环境会影响治疗反应。这表明 了解肿瘤细胞代谢的上下文相关变化可以使设计出更好的 利用转移部位的肿瘤细胞依赖性并改善癌症结果的治疗方法。 这项拟议的工作将评估组织环境等非遗传决定因素是否会改变新陈代谢 肿瘤细胞的依赖性。为了做到这一点，我将植入来自突变的Kras/P53-Null- 驱动小鼠非小细胞肺癌(NSCLC)或胰腺导管腺癌(PDAC)模型的建立 进入它们各自的起源组织和转移部位。然后我会研究这些区域的肿瘤新陈代谢 通过向清醒的小鼠注入标记的营养物质并追踪这些营养物质在TCA中的命运，来确定不同的部位 代谢物、核苷酸、蛋白质和类脂。我还将使用CRISPR/Cas9工具来消耗所需的酶 用于葡萄糖、谷氨酰胺和蛋白质摄取，并评估原发和转移部位的肿瘤形成。 这些研究的结果将首次表明癌细胞的新陈代谢依赖性是否会改变 取决于组织环境。这一点很重要，因为目前转移性疾病的治疗主要集中在原发肿瘤。 而不是转移性癌症的位置。这些实验将深入了解新陈代谢 适应是细胞固有的或由组织微环境介导的，并提高了我们对 转移性疾病。此外，这些研究可能揭示阻止转移性肿瘤生长的新方法。 基于阻断它们独特的新陈代谢途径。

Project Summary/Abstract Aberrant proliferation and altered metabolism are hallmarks of cancer cells. To proliferate, tumor cells must adapt their metabolism to acquire nucleotides, proteins, and lipids to support growth and division. Although altered metabolism to fulfill these biosynthetic needs is observed in all cancer cells, how metabolic demands are met in different tissue contexts and whether this affects the ability of cancer cells to proliferate in different metastatic sites is not well understood. This is particularly important as metastatic cancer is more difficult to treat than primary cancer, and tissue environment can influence response to therapy. This suggests that understanding context-dependent alterations in tumor cell metabolism could allow the design of better therapies that exploit tumor cell dependencies at metastatic sites and improve cancer outcomes. The proposed work will assess whether non-genetic determinants such as tissue context alter metabolic dependencies of tumor cells. To do this, I will implant cancer cells derived from either mutant Kras/p53-null- driven mouse models of non-small cell lung carcinoma (NSCLC) or pancreatic ductal adenocarcinoma (PDAC) into their respective tissue of origin and into metastatic sites. I will then study tumor metabolism in these different sites by infusing conscious mice with labeled nutrients and trace the fate of these nutrients into TCA metabolites, nucleotides, proteins, and lipids. I will also use CRISPR/cas9 tools to deplete enzymes required for glucose, glutamine, and protein uptake and assess tumor formation in primary and metastatic sites. The results of these studies will be the first to show whether metabolic dependencies of cancer cells change depending on tissue context. This is important, as current treatments for metastatic disease focus on primary cancer and not the location of metastatic cancer. These experiments will shed insight into whether metabolic adaptations are cell-intrinsic or mediated by the tissue microenvironment and improve our understanding of metastatic disease. Furthermore these studies may reveal new ways to block growth of metastatic tumors based on blocking their unique metabolic pathways.