Investigating the role of GAPDHS in melanoma metabolism and metastasis

项目摘要/摘要： 黑色素瘤是皮肤癌死亡的主要原因，因为它可以有效地转移到远处的器官。 转移需要显著的可塑性，癌细胞才能在有别于 原发肿瘤部位包括更高的氧化应激、有限的营养供应和变化 微环境。黑色素瘤经历这一过程所需的特定代谢变化很差。 明白了。我们最近发现了一种新的黑色素瘤转移抑制因子，甘油醛3-酶- 生精磷酸脱氢酶(GAPDHS)。我们描述了GAPDHS在一种 患者来源的异种移植(PDX)模型及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 确定其表达是否可用于预测黑色素瘤的肿瘤进展 病人。具体地说，我们将确定GAPDHS在中枢糖酵解中的酶活性是否 抑制转移所需(目标1)，如果其下游抑制丙酮酸羧基酶活性 影响转移(目标2)，以及GAPDHS的表达是否可作为黑色素瘤的生物标志物 患者的代谢和转移(目标3)。作为加州大学皮肤病学的助理教授 德克萨斯西南医学中心，在导师的指导下，我将80%的时间投入到我的研究兴趣中 拉尔夫·德贝拉迪尼斯博士，剩下的时间专门用于临床实践。我的目标是过渡到 作为一名成功的独立调查员，负责监督我自己的实验室和研究项目。至 实现这一目标，我正在寻求K08奖，以提供支持，以延长指导研究的时间，以 获得癌症新陈代谢、生物标记物开发和高级生物统计学的经验，这些都是 是实现我的研究目标所必需的。在一个杰出的指导委员会的指导下，我将 能够获得建立成功的独立研究所需的培训、资源和支持 该计划的重点是确定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.