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：
9109321
负责人：
Elena Piskounova
金额：
$ 11万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9109321
关键词：
Acetylcysteine Anoikis Antioxidants Biology Blood Blood Cells 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 Health 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 Outcome Oxidative Stress Pathway interactions Patients Pentosephosphate Pathway Phase Population Primary Neoplasm Process Proliferating Reactive Oxygen Species Reduced Glutathione Research Role Signal Pathway Signal Transduction Site Source Staging Stress Stress Response Signaling 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 shear stress 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（适用提供）：转移负责超过90％的癌症患者死亡率，但没有专门针对转移性疾病的疗法。当前许多转移的体外模型都集中在迁移，侵袭和/或存活的Anoikis的分子机制上，但不能概括体内转移发生的环境的复杂性。相反，在转移的小鼠模型中，很难检查使细胞能够通过每个不同转移步骤进行的分子机制。由于这些原因，关于体内转移细胞面临的挑战以及它们如何克服的挑战知之甚少。我的提议利用一种与免疫功能低下的小鼠中的黑色素瘤转移（患者衍生的Xenographtics）相关的临床相关模型，将转移性级联反应分为不同的步骤。在赠款的修补阶段，我将重点介绍在转移的不同阶段特有的代谢和应激信号传导途径，并在功能上验证其重要性。有了这些见解，我将继续独立研究，重点介绍这些瓶颈过程中参与的途径的分子细节，以识别可能证明对治疗转移性疾病有用的新型热靶标。