Cancer cell adaptation to metabolic stress

该计划的总体目标是确定肿瘤细胞对氧气和营养限制的适应的分子基础。当实体肿瘤内的细胞积累超过现有血管系统所能支持的生理数量时，就会出现氧气和/或营养缺乏。因此，发展中的肿瘤通常会受到氧气限制和营养缺乏的影响。在这些条件下，未转化细胞的积累受到抑制，因为缺氧/营养剥夺导致了细胞凋亡的启动。相反，大多数肿瘤细胞在其凋亡反应中存在缺陷，因此无法进行程序性细胞死亡。我们的中心假设是，肿瘤细胞既抑制细胞凋亡，又改变新陈代谢，以求存活，直到新血管生长。项目1的目标是确定允许肿瘤细胞在这些条件下适应和生长的代谢途径。该项目将确定细胞如何同时激活β-氧化以支持ATP的产生，同时保持细胞在缺糖期间生长所需的脂肪酸合成水平。项目1还将研究当缺氧诱导因子(HIF)激活导致有效葡萄糖从大分子合成转移到无氧糖酵解时，缺氧肿瘤细胞如何协调蛋白质和脂肪的合成。项目2中概述的实验将侧重于氧限制和HIF激活对c-Myc、mTOR和P53调节的代谢结果。HIF通过这些中枢调控途径影响转化细胞的合成代谢、增殖、蛋白质合成和DNA修复。项目3中提出的实验基于这样的假设，即PERK(作为细胞营养可获得性的传感器)通过激活转录程序而发挥关键的促生存因子的作用，该转录程序促进细胞对营养限制的适应，从而促进肿瘤的生长。在这个项目中，将评估PERK在调节氧化还原动态平衡和脂质生物合成方面的贡献。通过这个项目的协作，我们将研究葡萄糖限制(项目1)和缺氧(项目2)调节细胞对微环境的反应的机制。最后，将在项目3中评估这如何有助于氧化还原动态平衡和基因组完整性。所有三个项目都将经常使用代谢核心和行政核心，代谢核心将为细胞生物能量学的分析提供分析，行政核心将提供行政监督、预算管理和组织与外部咨询委员会的会议。在上一个供资周期中，所有三个项目之间已经建立了广泛的协作点。我们预计，我们的集体努力将为新陈代谢变化提供新的见解，这些变化是恶性细胞在氧气和养分供应减少的条件下适应的特征。

The overall goal of this program is to characterize the molecular basis for tumor cell adaptation to limitations in oxygen and nutrients. Oxygen and/or nutrient deprivation develops as cells within solid tumors accumulate in excess of physiological numbers supportable by the existing vascular system. Therefore, developing tumors are typically subjected to oxygen limitation and nutrient deprivation. The accumulation of non-transformed cells is inhibited under these conditions because hypoxia/nutrient deprivation leads to the initiation of apoptosis. In contrast, most tumor cells are defective in their apoptotic response, and therefore, fail to engage programmed cell death. Our central hypothesis is that tumor cells both suppress apoptosis and alter their metabolism to survive until new blood vessels grow. The goal of Project 1 is to identify metabolic pathways that allow tumor cells to adapt and grow under these conditions. This project will determine how cells simultaneously activate beta-oxidation to support ATP production while maintaining the level of fatty acid synthesis required for cell growth during glucose deprivation. Project 1 will also examine how hypoxic tumor cells coordinate protein and lipid synthesis when hypoxia inducible factor (HIF) activation results in diversion of available glucose away from macromolecular synthesis into anaerobic glycolysis. The experiments outlined in Project 2 will focus on metabolic outcomes of c-Myc, mTOR, and p53 modulation by oxygen limitation and HIF activation. HIFs influence anabolic metabolism, proliferation, protein synthesis, and DNA repair in transformed cells via these central regulatory pathways. Experiments proposed in Project 3 are based on the hypothesis that PERK (as a sensor of cellular nutrient availability) functions as a critical pro-survival factor via activation of a transcriptional program that promotes cellular adaptation to nutrient restriction thereby facilitating tumor growth. In this project, the contribution of PERK to the regulation of redox homeostasis and lipid biosynthesis will be evaluated. Through collaborations facilitated by this program project, we will investigate mechanisms whereby glucose limitation (Project 1) and oxygen deprivation (Project 2) regulate cellular responses to the microenvironment. Finally, how this contributes to redox homeostasis and genome integrity will be evaluated in Project 3. All three projects will make frequent use of the Metabolic Core which will provide assays for the analysis of cellular bioenergetics and an Administrative Core which will provide administrative oversight, budgetary management, and the organization of meetings with the external advisory board. Extensive points of collaboration have already been established between all three projects in the previous funding cycle. We anticipate that our collective efforts will provide novel insights into metabolic changes that characterize malignant cell adaptation under conditions of decreased oxygen and nutrient availability.