Cancer cell adaptation to metabolic stress

癌细胞对代谢应激的适应

基本信息

批准号：
8742517
负责人：
M. CELESTE SIMON
金额：
$ 117.33万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-10 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8742517
关键词：
Address Amino Acids Anabolism Apoptosis Autophagocytosis Biochemical Reaction Bioenergetics Blood Blood Vessels Cell Death Cell Survival Cell division Cells Citrates Collaborations Conventional (Clear Cell) Renal Cell Carcinoma Dependence Disease Progression Doctor of Medicine Doctor of Philosophy Elements Endoplasmic Reticulum Environment Exhibits Extracellular Fluid Fatty Acids Funding Generations Genes Glucose Glutamine Goals Growth Growth Factor Homeostasis Human Hypoxia Hypoxia Inducible Factor Investigation Laboratories Lesion Lipids Liquid substance Maintenance Malignant Epithelial Cell Malignant Neoplasms Mammalian Cell Mediating Melanoma Cell Metabolic Metabolic stress Metabolism Molecular Mus Mutation Nature Neoplastic Cell Transformation Nucleic Acids Nutrient Oncogenes Oncogenic Outcome Oxygen PERK kinase Pathway interactions Patients Phase Phenotype Phospholipids Phosphotransferases Process Proliferating Property Protein Biosynthesis Proteins Regulation Renal carcinoma Role Sampling Saturated Fatty Acids Serum Signal Transduction Solid Neoplasm Source Stearoyl-CoA Desaturase Stream Stress Stromal Cells Supporting Cell TSC2 gene Testing The Cancer Genome Atlas Therapeutic Tissues Tumor Suppressor Proteins Unsaturated Fats Unsaturated Fatty Acids biological adaptation to stress cancer cell cancer therapy cancer type cell growth cell transformation cell type cytotoxic deprivation extracellular fatty acid transport glucose transport insight macromolecule melanoma monounsaturated fat neoplastic cell new therapeutic target novel programs public health relevance research study response sensor tumor tumor initiation tumor microenvironment tumor progression tumorigenesis uptake water solubility

项目摘要

DESCRIPTION (provided by applicant): In nutrient replete conditions, cancer cells can synthesize lipids, nucleic acids, and other macromolecules from extracellular glucose and glutamine. However, as aggressive lesions overgrow the capacity of existing tumor vasculature to perfuse them, cells must adapt to decreased availability of O2 and blood-born nutrients (i.e. glucose, amino acids, and lipids) to survive and proliferate. Collectively, we have discovered novel mechanisms whereby multiple cancer cell types adapt to metabolic stress. Specifically, neither glucose- nor glutamine-derived citrate can support de novo fatty acid synthesis in hypoxic tumor microenvironments, due to the O2- dependence of stearoyl-CoA desaturase (SCD1)-mediated generation of monounsaturated lipids. Instead, hypoxic cancer cells obtain lipids from exogenous sources, such as the blood stream or extracellular fluid. While it has long been appreciated that SCD1 catalyzes O2-consuming enzymatic reactions, the observation that growing tumors exhibit regions where O2 levels decline below levels supporting SCD1 activity is novel. This metabolic stress results in a "maladaptive", cytotoxic Unfolded Protein Response (UPR) within the ER. In this Program, three integrated Projects will pursue the following specific aims to: Aim 1: Determine how Ras-transformed cells acquire exogenous unsaturated fatty acids; is "macropinocytosis" the relevant mechanism? Moreover, the role of autophagy components in Ras-mediated lipid utilization will be explored; Aim 2: Assess the impact of unsaturated: saturated fatty acid ratios on mTORC1- and pVHL-regulated cell survival under hypoxic conditions. Decreased levels of unsaturated fatty acids result in an UPR-mediated cell death, and this mechanism will be further explored in the "lipogenic" phenotype typical of ccRCC cells and primary patient samples; and Aim 3: Determine if PERK kinase inhibition represents an attractive therapeutic option for treating malignant melanoma. Apparently, incomplete PERK inhibition results in melanoma growth, while e 50% inhibition results in significant melanoma cell death. These findings are important because mutations in PERK functional domains have now been identified in human patient samples through TCGA efforts, including melanoma. Collectively, through these Projects and the Overall Program, we will define important new mechanisms by which cancer cells adapt to tumor microenvironmental stress, and determine whether these pathways can be targeted for anti-cancer treatment.

描述（由申请人提供）：在养分充气条件下，癌细胞可以从细胞外葡萄糖和谷氨酰胺中合成脂质，核酸和其他大分子。然而，随着侵略性病变过度生长了现有肿瘤脉管系统使其灌注它们的能力，细胞必须适应O2和血出生的养分（即葡萄糖，氨基酸和脂质）的可用性降低，以生存和增殖。总体而言，我们发现了新的机制，从而使多种癌细胞类型适应代谢应激。具体而言，由于硬氧肿瘤微环境中的葡萄糖 - 衍生的柠檬酸盐都无法支持从头脂肪酸的合成，这是由于stearoyl-COA去饱和酶（SCD1）介导的单不饱和脂质的产生的O2依赖性。取而代之的是，低氧癌细胞从外源性来源（例如血流或细胞外液）中获得脂质。虽然长期以来一直认为SCD1催化O2耗竭的酶促反应，但观察到生长肿瘤表现出的区域，其中O2水平下降到支持SCD1活性的水平以下是新颖的。这种代谢应激导致ER内的“适应不良”，细胞毒性展开的蛋白质反应（UPR）。在该计划中，三个集成项目将追求以下特定目标：AIM 1：确定RAS转换的细胞如何获得外源性不饱和脂肪酸； “大型细胞增多症”是相关机制吗？此外，将探索自噬成分在RAS介导的脂质利用率中的作用； AIM 2：评估不饱和的影响：在低氧条件下，饱和脂肪酸比对MTORC1和PVHL调节的细胞存活。不饱和脂肪酸水平降低导致UPR介导的细胞死亡，该机制将在CCRCC细胞和原发性患者样品的“脂肪生成”表型中进一步探索。 AIM 3：确定PERK激酶抑制是否代表治疗恶性黑色素瘤的有吸引力的治疗选择。显然，不完全的PERK抑制会导致黑色素瘤的生长，而E 50％的抑制作用会导致黑色素瘤细胞死亡。这些发现很重要，因为现在通过包括黑色素瘤在内的TCGA努力在人类患者样品中发现了PERK功能结构域中的突变。通过这些项目和整个计划，我们将定义重要的新机制，癌细胞适应肿瘤微环境应激，并确定是否可以将这些途径用于抗癌治疗。