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Identification and functional characterization of metabolic adaptations during melanoma metastasis

黑色素瘤转移过程中代谢适应的鉴定和功能表征

基本信息

批准号：
9526121
负责人：
Elena Piskounova
金额：
$ 24.9万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2016-04-15 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9526121
关键词：
Acetylcysteine Anoikis Antioxidants Biology Blood Blood Circulation Cancer Patient Cells Cessation of life Chronic Clinical Complex Data Disease Disease Outcome Disseminated Malignant Neoplasm Distant Distant Metastasis Environment Event Folic Acid Frequencies Genetic Glutathione Glutathione Disulfide Grant Growth Immunocompromised Host Laboratories Lesion Link Melanoma Cell Membrane Potentials Mentors Metabolic Metabolic Pathway Metabolic stress Metastatic Melanoma Mitochondria Modeling Molecular Mus NADP Natural regeneration Neoplasm Circulating Cells Neoplasm Metastasis Nodule Organ Oxidative Stress Pathway interactions Patients Pentosephosphate Pathway Pharmacology Phase Population Primary Neoplasm Process Proliferating Reactive Oxygen Species Reduced Glutathione Research Role Signal Pathway Signal Transduction Site Source Stress Testing Transplantation Visceral Work Xenograft procedure biological adaptation to stress cancer cell clinically relevant combat experience in vitro Model in vivo inhibitor/antagonist insight malic enzyme melanoma metabolomics migration mimetics mitochondrial membrane mortality mouse model mutant new therapeutic target novel peripheral blood predict clinical outcome public health relevance shear stress small hairpin RNA small molecule subcutaneous tool tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Metastasis is responsible for more than 90% of cancer patient mortality yet there are no therapies that specifically target metastatic disease. Many of the current in vitro models of metastasis focus on the molecular mechanisms of migration, invasion and/or surviving anoikis, but cannot recapitulate the complexity of the environment in which metastasis occurs in vivo. Conversely, in mouse models of metastasis, it has been difficult to examine the molecular mechanisms that enable cells to proceed through each distinct step of metastasis. For these reasons little is known about the challenges facing metastasizing cells in vivo, and how they are overcome. My proposal utilizes a clinically relevant model of melanoma metastasis, patient-derived xenografts in immunocompromised mice, to dissect the metastatic cascade into distinct steps. During the mentored phase of the grant, I will focus on identifying metabolic and stress-response signaling pathways that are specific to melanoma cells at different stages of metastasis, and functionally validate their importance. With these insights, I will continue independent research focusing on the molecular details of the pathways that are engaged during these bottlenecks to identify novel therapeutic targets that may prove useful in treating metastatic disease.

描述（由申请人提供）： 90% 以上的癌症患者死亡率是由转移造成的，但目前还没有专门针对转移性疾病的疗法。目前许多体外转移模型关注迁移、侵袭和/或失巢存活的分子机制，但不能概括体内转移发生环境的复杂性。相反，在小鼠转移模型中，很难检查使细胞能够完成转移的每个不同步骤的分子机制。由于这些原因，人们对体内转移细胞面临的挑战以及如何克服这些挑战知之甚少。我的建议利用临床相关的黑色素瘤转移模型，即免疫功能低下小鼠体内的患者来源的异种移植物，将转移级联分解为不同的步骤。在资助的指导阶段，我将专注于识别不同转移阶段黑色素瘤细胞特有的代谢和应激反应信号通路，并在功能上验证它们的重要性。有了这些见解，我将继续进行独立研究，重点关注这些瓶颈期间所涉及途径的分子细节，以确定可能对治疗转移性疾病有用的新治疗靶点。