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源和氮源形式的代谢途径来感知，而且通过紧密协调这些代谢底物的消耗与其他细胞过程控制的信号传导网络来感知。正是代谢和细胞生理学的其他方面（例如，细胞器生物发生、细胞周期进入等）使合成代谢细胞生长和增殖得以进行。然而，感知正常生长信号以协调调节生长过程（包括代谢）的相同信号网络也是人类癌症中最常见的受损信号网络，例如PI3K和Ras通路。雷帕霉素（mTOR）复合物1（mTORC 1）的机制靶标是细胞生长的主要调节剂和这些途径的共享下游效应子。mTORC1如何影响细胞生长的下游细胞过程尚未完全了解。我们实验室最近发表和未发表的数据表明，mTORC 1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，响应于生长信号，mTORC 1至少部分地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，mTORC 1在超过50%的人类癌症中被组成性激活，几乎跨越所有谱系。虽然现在已经认识到改变的细胞代谢是癌症的普遍特征，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，通过其下游控制蛋白质，脂质和核苷酸合成，是常见的致癌信号事件和癌细胞的合成代谢重编程之间的关键管道。这一提议扩展了我们之前关于mTORC 1通过转录因子SREBP家族诱导脂质合成（Aim 1）和通过S6 K1介导的CAD（该途径中的限速酶）磷酸化从头嘧啶合成（Aim 2）的机制研究。将确定致癌PI3K和Ras信号传导对mTORC 1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。在目标3下，我们将结合联合收割机特定的遗传和药理学扰动与无偏代谢组学，以表征PI3 K信号网络中新的mTORC 1或mTORC 2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 Recent published and unpublished data from our lab indicate that mTORC1, in addition to its established role in promoting protein synthesis, stimulates de novo synthesis of the two other major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.