Dietary methionine and cancer

营养素的可获得性（即饮食）可以影响代谢途径，并决定癌症的需求 细胞代谢到与肿瘤中重编程的代谢基因一样大的程度。 我们和其他人以前的工作表明，1。甲硫氨酸的有效性影响一个碳循环 通量，DNA和组蛋白甲基化，从而表观遗传编程，2.）蛋氨酸饮食限制 促进代谢健康，延长昆虫和哺乳动物的寿命，这两种抗癌表型， 3.）第三章在肿瘤中影响甲硫氨酸代谢的基因的缺失使它们易感。 然而，这种饮食因素（以及一般的饮食）如何影响癌症的结果在很大程度上是不确定的。 未知我们的初步数据表明，蛋氨酸限制延迟结直肠癌的肿瘤生长， 癌症患者来源的异种移植物（CRC PDX）模型并致敏基因工程小鼠 肉瘤模型进行放射治疗。这些发现促使我们提出一项调查， 这些表型背后的机制。我们将考虑以下目标。在目标1中， 鉴定对甲硫氨酸限制敏感性的分子决定因素。我们将采用代谢组学 我们实验室开发了一种使用代谢物分析平台和通量分析方法的方法 研究甲硫氨酸限制诱导的癌细胞代谢变化。我们将 接下来研究蛋氨酸代谢在肿瘤生长中的表观遗传作用。结果会 确定通过饮食蛋氨酸调节的代谢和表观遗传适应 新陈代谢.在目标2中，我们将确定为什么肉瘤对甲硫氨酸限制有抵抗力， 以协同方式对饮食蛋氨酸限制和辐射作出反应。结果将定义 代谢和表观遗传机制，发生，以抵制饮食操纵， 甲硫氨酸代谢，但导致饮食甲硫氨酸限制和辐射的协同作用。在 目的3，我们将确定蛋氨酸的作用，从饮食中的甲硫腺苷 磷酸化酶（MTAP）缺失的癌症。MTAP是蛋氨酸补救所必需的酶 最近的研究表明，MTAP中的缺失赋予了额外的依赖性， 甲基化反应。结果，使用MTAP，饮食蛋氨酸，蛋氨酸代谢作为一个指标， 模型系统将表征日粮蛋氨酸和MTAP之间的代谢相互作用 删除并导致对遗传和环境之间相互作用的新认识， 特别是饮食和营养在介导癌症结果中的作用。

Nutrient availability (i.e. diet) can affect metabolic pathways and determine the requirements of cancer cell metabolism to as large a degree as the metabolic genes that are reprogrammed in tumors. Previous work from us and others has shown that 1.) methionine availability affects one carbon cycle flux, DNA and histone methylation and thus epigenetic programming, 2.) dietary methionine restriction promotes metabolic health and extends insect and mammalian lifespan, two anti-cancer phenotypes, 3.) deletions of genes that affect methionine metabolism in tumors render them susceptible. Nevertheless, how this dietary factor (and diet in general) can influence cancer outcome is largely unknown. Our preliminary data shows that methionine restriction delays tumor growth in colorectal cancer patient derived xenograft (CRC PDX) models and sensitizes a genetically engineered mouse sarcoma model to radiation. These findings led us to propose an investigation to define the mechanisms underlying these phenotypes. We will consider the following aims. In aim 1 we seek to identify molecular determinants of sensitivity to methionine restriction. We will employ a metabolomics approach using a metabolite profiling platform and flux analysis method our laboratory has developed to investigate the metabolic changes in cancer cells that are induced by methionine restriction. We will next investigate the epigenetic role that methionine metabolism in tumor growth. The outcome will determine the metabolic and epigenetic adaptations that are modulated through dietary methionine metabolism. In aim 2, we will determine why the sarcomas are resistant to methionine restriction but respond to dietary methionine restriction and radiation in a synergistic manner. The outcome will define the metabolic and epigenetic mechanisms that occur in order to resist dietary manipulation of methionine metabolism but leads to a synergy effect of dietary methionine restriction and radiation. In aim 3, we will determine the role of methionine availability from diet in methylthioadenosine phosphorylase (MTAP)-deleted cancers. MTAP is an enzyme essential for the methionine salvage pathway and recent studies have shown that deletions in MTAP confer additional dependencies on methylation reactions. The outcome, using MTAP, dietary methionine, and methionine metabolism as a model system will characterize the metabolic interaction between dietary methionine and MTAP deletion and lead to a newfound understanding of the interaction between genetics and environment, particularly diet and nutrition in mediating cancer outcome.