Interaction between the Epitranscriptome and Metabolism in L-2HG Driven Kidney Cancer

项目总结。肾细胞癌(RCC)是两人最常见的10种恶性肿瘤之一 还有女人。虽然对于仅限于肾脏的肿瘤患者来说，结果是很好的，但 尽管有几种已获批准的治疗方法，但晚期疾病仍面临不利的结果。这强调了有必要 寻找新的治疗策略。我们确定了代谢物L-2-羟基戊二酸(L-2HG)的海拔高度 在相当大比例的农村信用社中。肿瘤代谢物是在癌症中异常积聚的小分子。 细胞，并能以多种方式影响肿瘤。我们的研究表明，L-2HG是RCC增长的强大驱动力 引导我们研究这种小分子发挥其致癌活性的机制。划定 这些效应将为治疗肿瘤代谢物驱动的肾癌提供新的策略。我们的初步研究已经 发现了两个新的发现。首先，L-2HG是表位编码组的强大调节者。尤其是，我们的 初步研究表明，L-2HG促进核糖核酸标志物N6-甲基腺苷的积聚 (M6A)。M6A是真核基因中最常见的核苷酸修饰，可以深刻地影响基因 表达(例如，信使核糖核酸稳定性、翻译)。第二，L-2HG重塑肿瘤代谢。我们引人入胜的 初步数据表明，这两个发现错综复杂地联系在一起，使我们提出了创新的 L-2HG诱导核糖核酸高甲基化改变新陈代谢以推动肿瘤生长的假说 代谢性负债。在目标1中，我们将确定L-2HG促进核糖核酸的分子基础 甲基化及其作用的功能意义。在目标2中，我们将剖析L- 2HG重塑新陈代谢，特别关注葡萄糖的利用及其对合成代谢活动的支持。在AIM 3、评价L-2HG诱导的代谢重塑对肿瘤生长的影响。此外，我们还将 确定这种重塑是否会造成新陈代谢脆弱性。利用我们在该领域的专业知识，我们将 纳入我们团队生成的新模型，并应用最先进的方法，如核糖体 用于L-2HG生物学研究的剖面图。提案工作意义重大，因为它可能会导致新的方法 以表位转录组和/或肿瘤新陈代谢为靶点。考虑到最近的证据，这项建议是及时的- 原则性研究表明，这些方法在药理学上是有针对性的。我们已经集合好了 成功完成拟议研究所需的多学科小组。考虑到流行程度 对于高L-2HG碾压混凝土，我们准备用将影响相当大比例的研究结果来推进这一领域 肾癌患者。

PROJECT SUMMARY. Renal cell carcinoma (RCC) is among the 10 most common malignancies in both men and women. Although outcomes are excellent for patients with tumors confined to the kidney, patients with advanced disease face unfavorable outcomes despite several approved therapies. This underscores the need for new treatment strategies. We have identified elevations of the oncometabolite L-2-hydroxyglutarate (L-2HG) in a significant proportion of RCCs. Oncometabolites are small molecules that aberrantly accumulate in cancer cells and can impact tumors in many ways. Our studies reveal that L-2HG is a potent driver of RCC growth leading us to investigate the mechanisms by which this small molecule exerts its oncogenic activity. Delineating these effects will inform novel strategies for oncometabolite-driven kidney cancer. Our preliminary studies have uncovered two novel findings. First, L-2HG is a powerful regulator of the epitranscriptome. In particular, our preliminary studies demonstrate that L-2HG promotes accumulation of the RNA mark, N6-methyladenosine (m6A). m6A is the most prevalent nucleotide modification in eukaryotic mRNA and can profoundly impact gene expression (e.g. mRNA stability, translation). Second, L-2HG remodels tumor metabolism. Our compelling preliminary data indicate that these two findings are intricately linked leading us to propose the innovative hypothesis that L-2HG induced RNA hypermethylation remodels metabolism to drive tumor growth but creates metabolic liabilities. In Aim 1 we will determine the molecular underpinning by which L-2HG promotes RNA methylation and the functional significance of this effect. In Aim 2, we will dissect the mechanisms by which L- 2HG remodels metabolism with specific focus on glucose utilization and its support of anabolic activities. In Aim 3, we will assess the impact of L-2HG induced metabolic remodeling on tumor growth. In addition, we will determine if this remodeling creates metabolic vulnerabilities. Leveraging our expertise in the field, we will incorporate novel models generated by our group and apply state of the art methodologies such as ribosome profiling to study the biology of L-2HG. The proposal work is significant as it will likely lead to novel approaches that target either the epitranscriptome and/or tumor metabolism. The proposal is timely given recent proof-of- principle studies demonstrating that these approaches are pharmacologically targetable. We have assembled a multidisciplinary team required for the successful completion of the proposed studies. Given the prevalence of high L-2HG RCC, we are poised to advance the field with findings that will impact a significant proportion of kidney cancer patients.