Regulation of Nutrient Stress-Induced Macropinocytosis in Pancreatic Ductal Adenocarcinoma

胰腺导管腺癌中营养应激诱导的巨胞饮作用的调节

基本信息

批准号：
9280912
负责人：
Cosimo Commisso
金额：
$ 44.61万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
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：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9280912
关键词：
Address Adenocarcinoma Cell Alleles Amino Acids Biological Assay Cancer Biology Cells Cellular Metabolic Process Clinical Consumption Data Dependency Disease EGFR inhibition Ecosystem Endocytosis Epidermal Growth Factor Receptor Evaluation Extracellular Protein Genetic Glutamine Goals Growth Guanosine Triphosphate HRAS gene Human Impairment In Vitro Intervention KRAS2 gene Lead Link Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Metabolic stress Molecular Nutrient Oncogenic Outcome Output Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Pharmacology Play Process Protein Isoforms Reaction Regulation Role Route Signal Pathway Signal Transduction Starvation Stress TP53 gene Testing Therapeutic Withdrawal Work base biological adaptation to stress cancer cell cancer therapy carcinogenesis cell growth cell transformation deprivation driving force drug discovery fitness in vivo mouse model mutant neoplastic cell new therapeutic target novel novel therapeutic intervention novel therapeutics pancreatic cancer cells pancreatic neoplasm response sensor tumor tumor growth tumor metabolism tumor microenvironment tumor progression tumorigenesis uptake

项目摘要

PROJECT SUMMARY Glutamine and other amino acids are important nutrients that support the metabolic and biosynthetic reactions necessary to sustain tumor growth. Elevated consumption rates by tumor cells can lead to a tumor ecosystem that is depleted of nutrients; however, tumors have the capacity to evolve metabolic adaptations that allow them to circumvent such nutrient stress. One such adaptation is the stimulation of macropinocytosis, an endocytic uptake mechanism that functions as an amino acid supply route in Ras-transformed cells. By enabling the uptake of extracellular protein and targeting it for lysosomal degradation, the macropinocytosis pathway supplies tumor cells with amino acids, allowing tumors to circumvent nutrient depletion and survive nutrient stress. Hence, the blockade of macropinocytosis represents a novel intervention strategy to starve tumor cells of nutrients; however, the signaling networks that control and regulate macropinocytosis in tumors are insufficiently understood. In this proposal, we will investigate the molecular mechanisms that drive macropinocytic induction in response to nutrient stress. Our preliminary data provide the first lines of evidence indicating that nutrient stress elicited by glutamine depletion has the ability to modulate macropinocytosis in a subset of Ras-transformed pancreatic cancer cells. This is important because pancreatic cancer has been recently recognized as a recalcitrant cancer that is in urgent need of new therapeutic strategies that offer an improvement in clinical outcome. We have attributed nutrient stress-induced macropinocytosis to the activation of the EGFR pathway and, importantly, we have implicated p53 as critical to controlling this EGFR-dependent uptake. In this proposal, we anticipate deciphering how this inducible form of macropinocytosis relies on EGFR and how this process is orchestrated by nutrient stress signals emanating from p53. Therefore, we will test the hypothesis that pancreatic tumors cope with nutrient stress by boosting their macropinocytic capacity, a process that is driven by EGFR signaling and p53. We will: (1) Determine the role of the EGFR signaling pathway in glutamine depletion-induced macropinocytosis; (2) Examine the functional interplay between oncogenic and wild-type Ras during nutrient stress; and (3) Decipher the function of p53 as a nutrient stress sensor that activates EGFR-dependent macropinocytosis. These aims will be investigated utilizing a combination of in vitro cell-based assays, human tumor interrogation, and mouse models of pancreatic cancer. In summary, our work could establish macropinocytosis as a critical metabolic adaptation that supports tumor cell fitness during pancreatic cancer progression and set the stage for new drug discovery efforts that exploit the nutrient dependencies of tumors.

项目概要谷氨酰胺和其他氨基酸是支持代谢和生物合成反应的重要营养素维持肿瘤生长所必需的。肿瘤细胞消耗率的升高可能会导致肿瘤生态系统的形成营养物质耗尽；然而，肿瘤有能力进化出代谢适应，从而允许他们来规避这种营养压力。其中一种适应是刺激巨胞饮作用，这是一种内吞摄取机制，在 Ras 转化细胞中充当氨基酸供应途径。经过能够摄取细胞外蛋白质并将其靶向溶酶体降解，即巨胞饮作用途径为肿瘤细胞提供氨基酸，使肿瘤能够避免营养耗尽并存活营养压力。因此，阻断巨胞饮作用代表了一种新的饥饿干预策略肿瘤细胞的营养物质；然而，控制和调节肿瘤巨胞饮作用的信号网络理解不够。在本提案中，我们将研究驱动的分子机制响应营养胁迫的巨胞饮诱导。我们的初步数据提供了第一线证据表明谷氨酰胺消耗引起的营养应激能够调节巨胞饮作用 Ras 转化的胰腺癌细胞的子集。这很重要，因为胰腺癌已最近被认为是一种顽固性癌症，迫切需要新的治疗策略来提供治疗临床结果的改善。我们将营养应激诱导的巨胞饮作用归因于激活 EGFR 通路的重要组成部分，重要的是，我们认为 p53 对于控制这种 EGFR 依赖性至关重要吸收。在本提案中，我们期望破译这种诱导形式的巨胞饮作用如何依赖于 EGFR 以及 p53 发出的营养应激信号如何协调这一过程。因此，我们将测试假设胰腺肿瘤通过增强其巨胞饮能力来应对营养应激，该过程由 EGFR 信号传导和 p53 驱动。我们将： (1) 确定 EGFR 信号传导的作用谷氨酰胺消耗诱导的巨胞饮作用途径； (2) 检查之间的功能相互作用营养胁迫期间的致癌和野生型 Ras； (3) 破译p53作为营养胁迫的功能激活 EGFR 依赖性巨胞饮作用的传感器。这些目标将利用结合体外细胞检测、人类肿瘤检查和胰腺癌小鼠模型。总之，我们的工作可以将巨胞饮作用确立为支持肿瘤的关键代谢适应胰腺癌进展期间的细胞适应性，并为新药发现工作奠定了基础肿瘤的营养依赖性。