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The Paradoxical Role of mTORC1 in the Growth of Nutrient-deprived Pancreatic Cancer Cells Harboring Ras Mutations

mTORC1 在携带 Ras 突变的营养剥夺胰腺癌细胞生长中的矛盾作用

基本信息

批准号：
9008439
负责人：
CRAIG B THOMPSON
金额：
$ 33.99万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9008439
关键词：
Adenocarcinoma Cell Albumins Amino Acids Apoptosis Autophagocytosis Binding Bioenergetics CRISPR screen Cell Cycle Arrest Cell Proliferation Cell Survival Cells Contrast Media Cytosol Data Environment Equilibrium Essential Amino Acids Event Expression Library Extracellular Protein Genetic Screening Genetic Transcription Genetically Engineered Mouse Glucose Glutamine Goals Growth HRAS gene Human In Vitro KRAS2 gene Knowledge Laboratories Leucine Lipids Lysosomes Malignant Neoplasms Malignant neoplasm of pancreas Mammalian Cell Mediating Metabolic Metabolic stress Metabolism Mutation Non-Essential Amino Acid Nucleic Acids Nutrient Oncogenic Open Reading Frames Pancreatic Ductal Adenocarcinoma Pathway interactions Phosphotransferases Production Proliferating Property Protein Biosynthesis Proteins Publications Recruitment Activity Regulation Repression Role Signal Transduction Sirolimus Source Testing Transfer RNA Work Xenograft procedure cancer cell cancer therapy cancer type cell growth cell transformation detection of nutrient extracellular glucose metabolism glucose uptake in vivo inhibitor/antagonist mTOR Inhibitor mTOR inhibition metaplastic cell transformation mouse model mutant neoplastic cell novel nutrient metabolism pancreatic cancer cells pancreatic neoplasm public health relevance research study response screening sensor small hairpin RNA tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Over the last decade we have demonstrated that one of the essential functions of growth factor signaling is to direct the cell to take up and metabolie nutrients. As a corollary, many cancer cells survive in the absence of growth factor signaling because of oncogenic mutations that stimulate nutrient uptake. In the past, we have established that Akt activation promoted cell survival by stimulating glucose uptake and metabolism. As a result, Akt-transformed cells become addicted to glycolytic metabolism for the support of ATP production and for the production of anabolic precursors. In addition, we discovered that Myc activation directs the uptake and metabolism of glutamine, which represents a second major metabolic substrate required for cell proliferation. When extracellular glucose and glutamine are abundant, cancer cells primarily synthesize lipids, nucleic acids, and non-essential amino acids from these precursors. Most cancer cells when deprived of glucose and/or glutamine undergo cell cycle arrest or apoptosis. Only a few cancer types, exemplified by pancreatic cancers, can continue to grow when their extracellular environment becomes depleted of these key metabolic substrates. Virtually every pancreatic cancer harbors a Ras mutation. Recently Ras-transformed pancreatic cancer cells were discovered to be able to proliferate in media depleted of either glutamine or essential amino acids. Ras-induced macropinocytosis allows pancreatic cancer cells to utilize extracellular proteins as a source of amino acids for continued protein synthesis. In studying this pathway, we have discovered that activated mTORC1 is a potent suppressor of the cellular utilization of extracellular proteins as a source of amino acids. In this proposal, we seek to further explore this paradoxical finding. Three Specific Aims are proposed: 1) Define the role of mTORC1 in the regulation of Ras-dependent protein uptake and degradation. 2) Determine the upstream regulators and downstream effectors of mTORC1-mediated suppression of extracellular protein uptake and degradation. 3) Determine if pharmacologic inhibition of mTOR can be combined with treatments that impair/exploit Ras-induced macropinocytosis in the therapy of genetically engineered mouse models of Ras-induced pancreatic ductal adenocarcinoma (PDAC) and human PDAC xenografts. Through these studies, we hope to elucidate a novel and underappreciated mechanism by which Ras-transformed cells adapt to metabolic stress and determine whether this pathway can be therapeutically exploited.

描述（由申请人提供）：在过去的十年中，我们已经证明生长因子信号传导的基本功能之一是指导细胞摄取和代谢营养物质。作为推论，许多癌细胞在缺乏生长因子信号传导的情况下存活，因为致癌突变刺激营养摄取。在过去，我们已经确定Akt激活通过刺激葡萄糖摄取和代谢促进细胞存活。因此，Akt转化的细胞变得依赖于糖酵解代谢，以支持ATP的产生和合成代谢前体的产生。此外，我们发现Myc活化指导谷氨酰胺的摄取和代谢，谷氨酰胺代表细胞增殖所需的第二种主要代谢底物。当细胞外葡萄糖和谷氨酰胺丰富时，癌细胞主要从这些前体合成脂质、核酸和非必需氨基酸。大多数癌细胞在缺乏葡萄糖和/或谷氨酰胺时经历细胞周期停滞或凋亡。只有少数癌症类型，例如胰腺癌，可以在细胞外环境耗尽这些关键代谢底物时继续生长。几乎每种胰腺癌都含有Ras突变。最近发现Ras转化的胰腺癌细胞能够在耗尽谷氨酰胺或必需氨基酸的培养基中增殖。Ras诱导的巨胞饮作用允许胰腺癌细胞利用细胞外蛋白作为氨基酸的来源，用于持续的蛋白质合成。在研究这一途径时，我们发现激活的mTORC 1是细胞利用胞外蛋白作为氨基酸来源的有效抑制剂。在本提案中，我们进一步探索这一矛盾的发现。本研究的目的有三：1）明确mTORC 1在Ras依赖性蛋白质摄取和降解中的作用。2)确定mTORC 1介导的细胞外蛋白摄取和降解抑制的上游调节因子和下游效应因子。3)确定在Ras诱导的胰腺导管腺癌（PDAC）和人PDAC异种移植物的基因工程小鼠模型的治疗中，mTOR的药理学抑制是否可以与损害/利用Ras诱导的巨胞饮作用的治疗相结合。通过这些研究，我们希望阐明Ras转化细胞适应代谢应激的一种新的和未被充分认识的机制，并确定这种途径是否可以用于治疗。