Investigating the role of GAPDHS in melanoma metabolism and metastasis

项目概要/摘要： 黑色素瘤是皮肤癌死亡的主要原因，因为它有效地转移到远处器官。 转移需要癌细胞具有显著的可塑性，才能在不同于癌细胞的代谢屏障中存活。 原始原发性肿瘤部位，包括较高的氧化应激，有限的营养供应， 微环境黑色素瘤经历这一过程所需的特定代谢变化很少 明白我们最近发现了一种新的黑色素瘤转移抑制剂，甘油醛3- 生精磷酸脱氢酶（GAPDHS）。我们描述了GAPDHS的功能作用， 患者来源的异种移植物（PDX）模型，并证明其对糖酵解和丙酮酸羧化酶的影响 活动在这项提案中，我们将研究与GAPDHS相关的代谢变化， 转移，并确定其表达是否可用于预测黑色素瘤中的肿瘤进展 患者具体地说，我们将确定在中枢糖酵解过程中GAPDHS的酶活性是否是 如果其下游抑制丙酮酸羧化酶活性， 影响转移（目的2），以及GAPDHS表达是否可作为黑色素瘤的生物标志物 代谢和转移的患者（目的3）。作为一个皮肤科的助理教授在大学的 德克萨斯州西南医学中心，我把80%的时间花在我的研究兴趣上， Ralph DeBerardinis博士，其余时间用于临床实践。我的目标是过渡到一个 作为一个成功的独立调查员，监督我自己的实验室和研究计划。到 为了实现这一目标，我正在寻求一个K08奖，为额外的指导研究提供支持， 获得癌症代谢，生物标志物开发和高级生物统计学的经验，这些都是 为了实现我的研究目标。在一个杰出的指导委员会的指导下，我将 有机会获得必要的培训，资源和支持，以建立一个成功的独立研究 该项目专注于识别黑色素瘤转移中的代谢脆弱性。

Project Summary/Abstract: Melanoma is the leading cause of skin cancer deaths because it metastasizes efficiently to distant organs. Metastasis requires significant plasticity for cancer cells to survive the metabolic barriers distinct from the original primary tumor site including higher oxidative stress, limited nutrient availability, and changing microenvironments. The specific metabolic changes required for melanoma to undergo this process are poorly understood. We recently identified a novel suppressor of melanoma metastasis, the enzyme glyceraldehyde 3- phosphate dehydrogenase, spermatogenic (GAPDHS). We characterized the functional role of GAPDHS in a patient-derived xenograft (PDX) model and demonstrated its impact on glycolysis and pyruvate carboxylase activity. In this proposal, we will investigate the metabolic changes associated with GAPDHS that drive metastasis and determine whether its expression can be used to predict tumor progression in melanoma patients. Specifically, we will determine whether the enzymatic activity of GAPDHS in central glycolysis is required for suppressing metastasis (Aim 1), if its downstream suppression of pyruvate carboxylase activity influences metastasis (Aim 2), and whether GAPDHS expression serves as a biomarker of melanoma metabolism and metastasis in patients (Aim 3). As an Assistant Professor of Dermatology at the University of Texas Southwestern Medical Center, I devote 80% of my time to my research interests under the mentorship of Dr. Ralph DeBerardinis, with the remaining time dedicated to clinical practice. My goal is to transition to a career as a successful independent investigator overseeing my own laboratory and research program. To achieve this, I am seeking a K08 award to provide support for an additional period of mentored research to gain experience with cancer metabolism, biomarker development, and advanced biostatistics, which are all necessary to achieve my research goals. With the guidance of a distinguished mentorship committee, I will have access to the training, resources, and support necessary to establish a successful independent research program focused on identifying metabolic vulnerabilities in melanoma metastasis.