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The Macropinosome: Uncovering the Molecular Anatomy of an Oncogene-driven Organelle

大胞饮体：揭示癌基因驱动细胞器的分子解剖结构

基本信息

批准号：
10153719
负责人：
Cosimo Commisso
金额：
$ 22.79万
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：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153719
关键词：
Actins Amino Acids Anabolism Anatomy Architecture Back Biological Assay Biological Markers Cancer Biology Carbon Catabolic Process Cell membrane Clinical Development Encapsulated Endocytic Vesicle Endocytosis Evaluation Event Extracellular Protein Fostering Goals Growth KRAS oncogenesis KRAS2 gene Liquid substance Lysosomes Malignant Neoplasms Mediating Membrane Metabolic Methodology Modeling Molecular Mutation Nanotechnology Nutrient Oncogenes Oncogenic Organelles Outcome Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Phase Positioning Attribute Process Production Proliferating Property Proteins Proteome Proteomics Regulation Role Route Signal Transduction Techniques Technology Therapeutic base cancer cell cancer therapy experimental study ferrite innovation insight knock-down metabolic fitness mutant nanoparticle neoplastic cell novel pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model precision medicine tumor tumor metabolism tumor microenvironment uptake

项目摘要

PROJECT SUMMARY As an integral aspect of the metabolic reprogramming that occurs in cancer, oncogenic KRAS mutations drive the stimulation of macropinocytosis, a type of endocytosis that mediates nonselective fluid-phase uptake. Using KRAS-driven models of pancreatic ductal adenocarcinoma (PDAC), we were the first to demonstrate that macropinocytosis functions in tumor cells as a nutrient acquisition pathway. Macropinocytosis triggers the internalization of extracellular proteins via discrete endocytic vesicles called macropinosomes. The incoming protein cargo is targeted for lysosome-dependent degradation, causing the intracellular release of amino acids. These protein-derived amino acids support metabolic fitness by contributing to the intracellular amino acid pools, as well as to the biosynthesis of central carbon metabolites. In this way, macropinocytosis represents a novel amino acid supply route that tumor cells use to survive the nutrient-poor conditions of the tumor microenvironment. While the tenets of the signal transduction events that drive macropinocytosis in cancer have emerged, a detailed picture of the macropinosome itself is not yet available. With the aid of nanotechnology, we have developed methodology to isolate a pure fraction of macropinosomes from PDAC cells. Having the capability to purify macropinosomes, we are now uniquely positioned to benefit from largescale proteomics that can provide a broad picture of this important organelle. By elucidating the molecular anatomy of KRAS-driven macropinosomes, we will gain further insight into the regulation and function of macropinocytosis in cancer. Moreover, having a clearer picture of the macropinosome will make us better positioned to exploit this pathway therapeutically and deliver breakthroughs to patients.

项目总结