Metabolic control of cell growth by the mTOR signaling network

描述（由申请人提供）：细胞生长条件不仅通过可用碳和氮源形式的代谢途径感知，而且通过信号网络紧密协调这些代谢底物的消耗和其他细胞过程的控制。正是这种代谢和细胞生理的其他方面（例如，细胞器生物发生，细胞周期进入等）的同步调节，使得合成代谢细胞的生长和增殖得以进行。然而，感知正常生长信号以协调调节包括代谢在内的生长过程的信号网络，也是人类癌症中最常被破坏的信号网络，如PI3K和Ras通路。雷帕霉素（mTOR）复合物1 （mTORC1）的机制靶点是细胞生长的主要调节因子，也是这些途径的共同下游效应因子。mTORC1如何影响细胞生长的下游细胞过程尚不完全清楚。我们实验室最近发表的和未发表的数据表明，mTORC1除了在促进蛋白质合成方面的既定作用外，还刺激细胞的另外两个主要组成部分，脂质和核苷酸的从头合成。因此，在响应生长信号时，mTORC1至少在一定程度上通过诱导关键的合成代谢过程来促进细胞生长。由于大量的上游癌基因和肿瘤抑制因子，mTORC1在几乎所有谱系中超过50%的人类癌症中被组成性激活。虽然现在人们已经认识到细胞代谢的改变是癌症的普遍特征，但致癌途径如何促进驱动细胞自主生长的代谢变化在很大程度上是未知的。在这里，我们假设mTORC1通过其下游对蛋白质、脂质和核苷酸合成的控制，是常见致癌信号事件和癌细胞合成代谢重编程之间的关键通道。该建议扩展了我们之前关于mTORC1通过SREBP转录因子家族诱导脂质合成的机制研究（Aim 1）和通过s6k1介导的CAD磷酸化（该途径中的限速酶）重新合成嘧啶的机制研究（Aim 2）。将确定致癌PI3K和Ras信号对mTORC1下游脂质和核苷酸合成的影响。我们还将确定这些mtorc1刺激的细胞代谢变化在促进细胞生长和肿瘤发生中的作用。在Aim 3下，我们将结合特定的遗传和药理学扰动与无偏倚代谢组学来表征PI3K信号网络中新的mTORC1或mtorc2依赖性代谢调节点。在所有这些研究中，我们将采用基于细胞的系统和小鼠肿瘤模型，重点是定义癌细胞代谢控制的分子机制，并以靶向关键代谢酶和脆弱性的形式确定治疗机会，以选择性地杀死癌细胞。

DESCRIPTION (provided by applicant): Cellular growth conditions are sensed not only by metabolic pathways in the form of available carbon and nitrogen sources but also by signaling networks that tightly coordinate the consumption of these metabolic substrates with the control of other cellular processes. It is this coincident regulation of metabolism and other aspects of cell physiology (e.g., organelle biogenesis, cell-cycle entry, etc.) that allows anabolic cell growh and proliferation to proceed. However, the same signaling networks that perceive normal growth signals to coordinately regulate growth processes, including metabolism, are also those most commonly corrupted in human cancers, such as the PI3K and Ras pathways. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cell growth and a shared downstream effector of these pathways. How mTORC1 influences the downstream cellular processes underlying cell growth is not fully understood. Recent published and unpublished data from our lab indicate that mTORC1, in addition to its established role in promoting protein synthesis, stimulates de novo synthesis of the two other major building blocks of the cell, lipids and nucleotides. Therefore, in response to growth signals, mTORC1 promotes cell growth, at least in part, by inducing key anabolic processes. Due to a large number of upstream oncogenes and tumor suppressors, mTORC1 is constitutively activated in over 50% of human cancers, across nearly all lineages. While it is now well recognized that altered cellular metabolism is a ubiquitous feature of cancer, how oncogenic pathways promote the metabolic changes that drive cell autonomous growth is largely unknown. Here, we hypothesize that mTORC1, through its downstream control of protein, lipid, and nucleotide synthesis, is a key conduit between common oncogenic signaling events and the anabolic reprogramming of cancer cells. This proposal extends our previous mechanistic studies on mTORC1 inducing lipid synthesis through the SREBP family of transcription factors (Aim 1) and de novo pyrimidine synthesis through the S6K1-mediated phosphorylation of CAD, the rate-limiting enzyme in this pathway (Aim 2). The effects of oncogenic PI3K and Ras signaling on lipid and nucleotide synthesis downstream of mTORC1 will be determined. We will also establish the role of these mTORC1-stimulated changes in cellular metabolism in promoting cell growth and tumorigenesis. Under Aim 3, we will combine specific genetic and pharmacological perturbations with unbiased metabolomics to characterize novel mTORC1- or mTORC2-dependent points of metabolic regulation within the PI3K signaling network. In all of these studies, we will employ both cell-based systems and mouse tumor models, with an emphasis on defining molecular mechanisms of metabolic control in cancer cells and the identification of therapeutic opportunities in the form of targeting key metabolic enzymes and vulnerabilities to selectively kill cancer cells.