Identifying factors regulating cancer metabolism in vivo

项目摘要 新陈代谢改变是恶性肿瘤的一个标志。代谢途径的改变有助于癌细胞的生长， 转型和生存。这些差异可以被利用来对肿瘤组织进行成像，并提供预测 将信息传递给患者。重要的是，这些新陈代谢的差异也可以用来治疗。因此， 了解肿瘤代谢对病理生理学和临床肿瘤学具有重要意义。 将这些研究转化为新疗法的进展受到以下事实的限制：许多关于肿瘤的知识 新陈代谢来源于对培养细胞的研究，但与疾病生物学的相关性尚不清楚。类似地，单元格 LINE异种移植可能不能准确地概括原发肿瘤的细胞异质性。出于这些原因， 人们对肿瘤在体内的代谢以及调节这种行为的因素知之甚少。我的建议是利用 对原发人类肿瘤的代谢行为进行评估和表征的临床样本。 这些组织被转化到小鼠模型中，在那里我将评估保留了哪些代谢表型， 以及测试哪些内在和外在因素促进新陈代谢行为。在指导阶段， 格兰特，我将专注于确定保留/内在代谢表型，以及外部因素，如 肿瘤血流灌注对营养偏好的影响。有了这些见解，我将继续独立研究，专注于 关于这些因素的分子细节，以确定影响癌症代谢的因素组合 活着。

Project Summary Altered metabolism is a hallmark of malignancy. Metabolic pathway changes contribute to cancer cell growth, transformation and survival. These differences can be exploited to image tumor tissue and provide predictive information to patients. Importantly, these metabolic differences can also be exploited therapeutically. Thus, understanding cancer metabolism has important implications for pathophysiology and clinical oncology. Progress in translating these studies into new therapies is limited by the fact that much of knowledge in tumor metabolism is derived from studies in cultured cells with unknown relevance to disease biology. Similarly, cell line xenografts may not accurately recapitulate the cellular heterogeneity of a primary tumor. For these reasons, little is known about tumor metabolism in vivo, and the factors that regulate this behavior. My proposal utilizes clinical samples wherein the metabolic behavior of the primary human tumor is evaluated and characterized. These tissues are translated to mouse models, where I will evaluate what metabolic phenotypes are retained, as well as test what intrinsic and extrinsic factors promote metabolic behavior. During the mentored phase of the grant, I will focus on identifying retained/intrinsic metabolic phenotypes, as well as extrinsic factors such as the role of tumor perfusion on nutrient preference. With these insights, I will continue independent research focusing on the molecular details of these factors, to identify combinations of factors influencing cancer metabolism in vivo.