Understanding cell intrinsic and context dependent metabolic adaptations of cancer cell

了解癌细胞的细胞内在和环境依赖性代谢适应

• 批准号: 9320007
• 负责人: LAURA VICTORIA DANAI
• 金额: $ 3.28万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9320007
• 关键词: Address; Adipocytes; Affect; Albumins; Biogenesis; CRISPR/Cas technology; Cancer Cell Growth; Catabolism; Cells; Conscious; DNA; Dependence; Dependency; Disease; Disseminated Malignant Neoplasm; Environment; Enzymes; Genetic; Glucose; Glutaminase; Glutamine; Growth; Implant; Label; Light; Lipids; Location; Lung Neoplasms; Lysosomes; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Nucleotides; Nutrient; Organ; Outcome; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Primary Neoplasm; Proliferating; Proteins; Pyruvate Carboxylase; Resistance; Site; TP53 gene; Testing; Tissues; Tumor Initiators; Tumor-Derived; Work; base; cancer cell; chemotherapy; design; experimental study; genetic manipulation; genetically modified cells; genome editing; improved; insight; macromolecule; mouse model; mutant; neoplastic cell; non-genetic; outcome forecast; response; tool; transcription factor; tumor; tumor growth; tumor metabolism; tumor microenvironment; uptake

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.

项目概要/摘要 异常增殖和代谢改变是癌细胞的标志。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、蛋白质和脂质来支持生长和分裂。虽然 在所有癌细胞中都观察到为了满足这些生物合成需求而改变代谢，代谢需求如何 在不同的组织环境中得到满足，这是否会影响癌细胞在不同组织中增殖的能力 转移部位尚不清楚。这一点尤其重要，因为转移性癌症更难以治疗 治疗比原发性癌症要好，组织环境可以影响对治疗的反应。这表明 了解肿瘤细胞代谢的背景依赖性改变可以帮助设计更好的 利用转移部位肿瘤细胞依赖性并改善癌症结果的疗法。 拟议的工作将评估非遗传决定因素（例如组织背景）是否会改变代谢 肿瘤细胞的依赖性。为此，我将植入来自突变体 Kras/p53-null- 的癌细胞。 非小细胞肺癌（NSCLC）或胰腺导管腺癌（PDAC）驱动的小鼠模型 进入各自的起源组织和转移部位。然后我将研究这些中的肿瘤代谢 通过向有意识的小鼠注入标记的营养物质来研究不同部位，并追踪这些营养物质进入 TCA 的命运 代谢物、核苷酸、蛋白质和脂质。我还将使用 CRISPR/cas9 工具来耗尽所需的酶 用于葡萄糖、谷氨酰胺和蛋白质的摄取，并评估原发部位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代谢依赖性是否发生变化 取决于组织环境。这很重要，因为目前转移性疾病的治疗集中于原发性疾病 癌症而不是转移癌的位置。这些实验将深入了解代谢是否 适应是细胞固有的或由组织微环境介导的，并提高我们对 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 基于阻断其独特的代谢途径。