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

基本信息

批准号：
10401910
负责人：
Christian Michael Metallo
金额：
$ 41.46万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
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/10401910
关键词：
Alanine Amino Acids Anabolism Anchorage-Independent Growth Antineoplastic Agents Breast cancer metastasis Cancer Cell Growth Carbon Cell Culture Techniques Cell Proliferation Clinic Colon Carcinoma Data Diet Dietary Intervention Engineering Environment Enzymes Exhibits Extracellular Matrix Genetic Glycine Growth Hereditary Sensory Neuropathy In Vitro Link Lipids Maintenance Metabolic Metabolic Pathway Metabolism Methods Mitochondria Multienzyme Complexes Neoplasm Metastasis Non-Essential Amino Acid Nucleotides Oncogenic Oxidation-Reduction Oxidoreductase Pathway interactions Patients Pharmacology Phosphatidylserines Play Process Production Proliferating Protein Biosynthesis Pyruvate Pyruvate Kinase Pyruvate Metabolism Pathway Regulation Role Serine Signaling Molecule Sphingolipids Sphingomyelins Supplementation Testing Therapeutic Work Xenograft procedure amino acid metabolism base breast cancer progression cancer cell carboxylation cell growth deprivation design dietary dietary manipulation dietary restriction improved in vivo in vivo Model inhibitor lipid biosynthesis lipid metabolism lipidomics metabolic abnormality assessment mitochondrial metabolism neoplastic cell novel overexpression public health relevance pyruvate carrier pyruvate dehydrogenase response serine palmitoyltransferase sphingosine 1-phosphate tumor tumor growth tumor metabolism tumor progression tumorigenesis

项目摘要

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.

抽象的癌细胞重新编程的代谢途径，以响应其变化而生存和增殖微环境。而致癌途径维持糖酵解代谢，以增强在肿瘤发生后，线粒体代谢在丧失细胞外基质（ECM）接触后会显着改变和与锚固无关的条件下的生长。通过将代谢通量分析（MFA）应用于肿瘤球体，我们已经确定了控制丝氨酸，丙氨酸和鞘脂代谢的特殊变化这种微环境中的肿瘤细胞生长。许多肿瘤会扩增或过表达磷酸羟甲酸而望丝氨酸合成途径以支持生长的脱氢酶（PHGDH）和其他酶该途径支持攻击性肿瘤生长的特定机制尚不清楚。丝氨酸和丙氨酸代谢通过鞘脂生物合成链接，其中酶丝氨酸棕榈酰转移酶（SPT）在丰富的丙氨酸和低丝氨酸水平的背景下产生有毒的脱氧脂脂（DOXSL）。这些非典型的doxSL在锚定的生长和妥协期间以较高的速率产生线粒体代谢可减轻球体生长。通过调节丝氨酸的生产和可用性，我们可以控制体外和体内肿瘤生长的丙氨酸和鞘脂。这些发现提供了小说，丝氨酸剥夺限制癌细胞生长的未开发机制。该建议旨在利用通过操纵饮食氨基酸和内源性丝氨酸合成与肿瘤中DOXSL的产生减轻肿瘤生长和转移。在AIM 1中，我们将使用MFA来表征线粒体和在锚固非依赖性生长过程中，氨基酸途径。在AIM 2中，我们将量化鞘脂生物合成在球体生长过程中受到影响，并确定为什么DoxSL物种对肿瘤细胞有毒。在 AIM 3我们将设计专门配制的饮食，通过调节DOXSL来减轻肿瘤的生长和转移单独给药或与PHGDH抑制剂结合使用时产生。我们还将设计肿瘤细胞中的鞘脂生物合成途径以验证我们的中心假设。如果成功，这个建议将定义一种新的机制，丝氨酸剥夺限制了可以通过饮食干预措施，用于鉴定诊所中的反应性肿瘤类型。