Linking Oncogenic Signaling to Tumor Metabolism

 描述(由申请人提供)：癌细胞改变其代谢程序以维持细胞的自主增殖。肿瘤细胞生物能量学的一些最显著的变化包括糖酵解增加，谷氨酰胺分解通量增加，氨基酸和脂肪代谢上调，线粒体生物合成增强，磷酸戊糖途径和大分子生物合成的诱导。我对代谢调节和癌症的兴趣促使我进行了关于代谢应激诱导剂在前列腺癌细胞存活中的作用的博士研究。我的博士工作帮助理解了代谢扰动对癌细胞活性的作用，我们是世界上第一批发现抗糖尿病药物二甲双胍的抗癌特性的小组之一。我的博士后工作揭示了mTORC1信号和代谢途径之间的新联系。我们发现，通过生理或致癌刺激激活mTORC1，导致代谢流量的急性刺激，通过从头开始的嘧啶合成途径，这有助于制造合成代谢细胞生长和增殖所需的RNA和DNA的积木。MTORC1信号转译后通过其下游靶标核糖体蛋白S6激酶1(S6K1)调节这一代谢途径，S6K1直接使Ser1859在CAD(氨基甲酰-磷酸合成酶2，天冬氨酸转氨甲酰基酶，二氢酶)上磷酸化，CAD是催化从头合成嘧啶的前三步的酶。我的目标是研究细胞代谢和致癌事件之间的分子联系。最终，我的长期职业目标是在一家学术机构获得一个终身教职的职位，在那里我将能够扩大我的研究领域，培训和指导研究生和本科生，并与我的学术同行合作。在这项应用的指导阶段提出的研究将集中在CAD的Ser1859磷酸化在肿瘤代谢中的作用以及mTORC1在从头合成嘌呤中的作用。在独立阶段概述的研究将寻求确定致癌和生理信号与从头开始和挽救核苷酸合成之间的新联系，以揭示特定杀死肿瘤细胞的潜在治疗靶点。癌细胞表现出非典型代谢特征的初步发现可以追溯到 奥托·沃堡在二十世纪上半叶的开创性工作。破译致癌过程和代谢途径之间的相互作用有助于在给定的环境下进行代谢重新编程，这可能是确定治疗靶点的关键因素，从而能够在对正常细胞的有害影响最小的情况下实现最大的药物疗效。最终，我的研究提案将理想地促进利用癌症中非典型代谢特征作为治疗干预手段的进一步进展。

 DESCRIPTION (provided by applicant): Cancer cells alter their metabolic program to maintain cell autonomous proliferation. Some of the most striking changes of tumor cellular bioenergetics include elevation of glycolysis, increased glutaminolytic flux, up- regulation of amino acid and lipid metabolism, enhancement of mitochondrial biogenesis, induction of the pentose phosphate pathway and macromolecule biosynthesis. My interest in metabolic regulation and cancer led me to undertake my PhD study on the role of metabolic stress inducing agents in prostate cancer cell survival. My PhD work helped to understand the role of metabolic perturbations on cancer cell viability and we were among the first groups in the world to uncover the anti-cancer properties of the anti-diabetic drug metformin. My postdoctoral work revealed a new connection between mTORC1 signaling and metabolic pathways. We showed that mTORC1 activation via a physiological or an oncogenic stimulus, led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway, which serves to make building blocks of RNA and DNA required for anabolic cell growth and proliferation. mTORC1 signaling post-translationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates Ser1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), an enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. My goal is to investigate the molecular links between cellular metabolism and oncogenic events. Ultimately, my long-term career goal is to obtain a tenure-track faculty position at an academic institution where I will be able to expand my area of research, train and instruct graduate and undergraduate students and collaborate with my academic peers. The research proposed in the mentored phase of this application will focus on the role of Ser1859 phosphorylation of CAD in tumor metabolism and the role of mTORC1 on de novo purine synthesis. The research outlined in the independent phase will seek to identify novel connections between oncogenic and physiological signals and the de novo and salvage nucleotide synthesis to uncover a potential therapeutic target to specifically kill tumor cells. Th initial discovery that cancer cells exhibit atypical metabolic characteristics can be traced to the pioneering work of Otto Warburg, over the first half of the twentieth century. Deciphering the interplay between oncogenic processes and metabolic pathways that contribute to metabolic reprogramming in a given setting may serve as the critical factor in determining therapeutic targets that enable maximal drug efficacy with minimal deleterious effect on normal cells. Ultimately, my research proposal will ideally facilitate further progress in capitalizing upon the exploitation of atypical metabolic features in cancer as a means of therapeutic intervention.