Non-essential amino acids and sphingolipid diversity in cancer progression

癌症进展中的非必需氨基酸和鞘脂多样性

• 批准号: 10555142
• 负责人: Christian Michael Metallo
• 金额: $ 23.51万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10555142
• 关键词: Non; essential; amino; acids; sphingolipid

Abstract Cancer cells reprogram metabolic pathways to survive and proliferate in response to changes in their microenvironment. While oncogenic pathways sustain glycolytic metabolism to enhance survival during tumorigenesis, mitochondrial metabolism is significantly altered upon loss of extracellular matrix (ECM) contact and growth under anchorage-independent conditions. By applying metabolic flux analysis (MFA) to tumor spheroids, we have identified particular changes in serine, alanine, and sphingolipid metabolism that control tumor cell growth in such microenvironments. Many tumors amplify or overexpress phosphohydroxypyruvate dehydrogenase (PHGDH) and other enzymes within the serine synthesis pathway to support growth, though the specific mechanisms through which this pathway supports aggressive tumor growth remain unclear. Serine and alanine metabolism are linked via sphingolipid biosynthesis, where the enzyme serine palmitoyltransferase (SPT) produces toxic deoxysphingolipids (doxSLs) in the context of abundant alanine and low serine levels. These atypical doxSLs are produced at higher rates during anchorage-independent growth and compromise mitochondrial metabolism to mitigate spheroid growth. By modulating the production and availability of serine, alanine, and sphingolipids we can control in vitro and in vivo tumor growth. These findings provide a novel and unexplored mechanism through which serine deprivation limits cancer cell growth. This proposal aims to exploit the production of doxSLs in tumors by manipulating dietary amino acids and endogenous serine synthesis to mitigate tumor growth and metastasis. In Aim 1 we will apply MFA to characterize changes in mitochondrial and amino acid pathways during anchorage-independent growth. In Aim 2 we will quantify how sphingolipid biosynthesis is impacted during spheroid growth and determine why doxSL species are toxic to tumor cells. In Aim 3 we will design specifically formulated diets that mitigate tumor growth and metastasis by modulating doxSL production when administered alone or in combination with PHGDH inhibitors. We will also engineer the sphingolipid biosynthesis pathway in tumor cells to validate our central hypothesis. If successful, this proposal will define a novel mechanism through which serine deprivation limits tumor growth that can be exploited via dietary interventions and used to identify responsive tumor types in the clinic.

摘要 癌细胞重新编程代谢途径以生存和增殖，以响应其变化 微环境。虽然致癌途径支持糖酵解代谢以提高存活率 肿瘤发生，线粒体代谢在失去细胞外基质(ECM)接触后显著改变 在不依赖锚地的条件下生长。将代谢流分析(MFA)应用于肿瘤 球体，我们已经确定了控制丝氨酸、丙氨酸和鞘磷脂代谢的特殊变化 肿瘤细胞在这样的微环境中生长。许多肿瘤放大或过度表达磷酸羟丙酮酸 脱氢酶(PHGDH)和丝氨酸合成途径中的其他酶支持生长，尽管 这一途径支持侵袭性肿瘤生长的具体机制尚不清楚。丝氨酸和 丙氨酸代谢通过鞘磷脂的生物合成联系在一起，其中丝氨酸棕榈酰基转移酶 (SPT)在富含丙氨酸和低丝氨酸水平的情况下产生有毒的脱氧鞘磷脂(DoxSLs)。 这些非典型的doxSLs在锚地独立的生长和妥协期间以更高的速率产生 线粒体代谢，以减缓球体的生长。通过调节丝氨酸的生产和可利用性， 丙氨酸和鞘磷脂我们可以在体外和体内控制肿瘤的生长。这些发现提供了一种新颖的和 丝氨酸缺乏限制癌细胞生长的未知机制。这项提议旨在利用 通过调节膳食氨基酸和内源性丝氨酸合成在肿瘤中产生doxSLs 减少肿瘤生长和转移。在目标1中，我们将应用MFA来表征线粒体和 非锚定生长过程中的氨基酸途径。在目标2中，我们将量化鞘脂如何 生物合成在球体生长过程中受到影响，并决定了doxSL物种对肿瘤细胞有毒的原因。在……里面 目的3我们将设计特定配方的饮食，通过调节doxSL来减轻肿瘤的生长和转移 当单独给药或与PHGDH抑制剂联合使用时产生。我们还将设计 肿瘤细胞中鞘磷脂的生物合成途径来验证我们的中心假设。如果成功，这项提案 将定义一种新的机制，通过这种机制，丝氨酸缺乏可以限制肿瘤的生长，可以通过 饮食干预，并用于在临床上识别有反应的肿瘤类型。