Tumor Cell Dependence on Host Metabolism

肿瘤细胞对宿主代谢的依赖性

基本信息

批准号：
9333585
负责人：
JOSHUA D RABINOWITZ
金额：
$ 44.07万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-07 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9333585
关键词：
Address Amino Acids Anabolism Antineoplastic Agents Arginine Autophagocytosis Biomass Blood Circulation Bypass Characteristics Consumption Dependence Dependency Diet Dietary Intervention Explosion Fatty Acids Fatty acid glycerol esters Fermentation Generations Genetic Glucose Glutamine Glutathione Glycine Growth Homeostasis Impairment Implant In Vitro Intake Isotopes K-ras mouse model Malignant Neoplasms Malignant neoplasm of lung Maps Metabolic Metabolic Pathway Metabolism Methionine Methods Modeling Molecular Monitor Mus NADP Non-Essential Amino Acid Normal tissue morphology Nucleotides Nutrient Nutritional Support Oxidation-Reduction Pathway interactions Plasma Play Role Route Serine Source Techniques Testing Therapeutic Time Tissues Tracer Treatment Protocols Vascular blood supply Warburg Effect Work asparaginase cancer cell cancer therapy clinical efficacy comparative design in vivo interest invention melanoma metabolomics neoplastic cell novel strategies response tumor tumor growth tumor metabolism uptake

Address Amino Acids Anabolism Antineoplastic Agents Arginine Autophagocytosis Biomass Blood Circulation Bypass Characteristics Consumption Dependence Dependency Diet Dietary Intervention Explosion Fatty Acids Fatty acid glycerol esters Fermentation Generations Genetic Glucose Glutamine Glutathione Glycine Growth Homeostasis Impairment Implant In Vitro Intake Isotopes K-ras mouse model Malignant Neoplasms Malignant neoplasm of lung Maps Metabolic Metabolic Pathway Metabolism Methionine Methods Modeling Molecular Monitor Mus NADP Non-Essential Amino Acid Normal tissue morphology Nucleotides Nutrient Nutritional Support Oxidation-Reduction Pathway interactions Plasma Play Role Route Serine Source Techniques Testing Therapeutic Time Tissues Tracer Treatment Protocols Vascular blood supply Warburg Effect Work asparaginase cancer cell cancer therapy clinical efficacy comparative design in vivo interest invention melanoma metabolomics neoplastic cell novel strategies response tumor tumor growth tumor metabolism uptake

展开

项目摘要

ABSTRACT Rapid fermentation of glucose to lactate (the “Warburg effect”) was the first molecular characteristic assigned to cancer. Recent years have seen an explosion of interest in the metabolic capabilities of tumor cells, including up-regulated anabolism, redox defense, and alternative routes of nutrient acquisition such as macropinocytosis and autophagy. While these cellular capabilities play a critical role, metabolically, tumors ultimately depend on circulating nutrients provided by the host. The extent to which tumors generate energy and biomass building blocks from a few preferred circulating nutrients like glucose, versus uptake diverse nutrients to minimize their own biosynthetic work, remains, however, poorly understood. For example, many tumors upregulate serine biosynthesis. At the same time, tumor growth is sensitive to dietary serine intake. Which contributes more—circulating serine from the diet or serine synthesized in the tumor? While substantial efforts have been made to understand the essential metabolic pathways within tumor cells, comparatively little effort has gone into understanding the tumor's dependency on host metabolism. We have surprisingly observed that consumption of circulating nutrients by tumors is profoundly different from that of cultured cancer cells. We have also surprisingly observed that host autophagy is important for sustaining circulating nutrients and for the growth of implanted tumors (where autophagy remains intact). These findings highlight the potential for host metabolic processes to impact tumor growth. What are the critical circulating nutrients for tumors? How is host metabolism altered by autophagy deficiency? Which are the critical changes that impair tumor growth? More broadly, how can tumor dependency on host metabolism be exploited therapeutically? To address these questions, we will employ state-of-the-art isotope tracer techniques to murine tumor models of lung cancer and melanoma. Specifically, we will address the role of host metabolism in mouse models of K-Ras lung cancer, and B-Raf lung cancer and melanoma: Aim 1: Identify the contributions of circulating nutrients and internal tumor metabolic pathways to lung cancer and melanoma growth. We hypothesize that, rather than using glucose and glutamine as their primary substrates, tumors in vivo consume a broad diversity of circulating nutrients, including amino acids, fats, and lactate, thereby minimizing biosynthetic requirements and enhancing metabolic robustness. Aim 2: Determine the mechanism underlying dependence of tumors on host autophagy. We hypothesize that host autophagy is required to maintain circulating nutrients to support tumor growth. Aim 3: Assess the therapeutic potential of modulating circulating metabolites. We hypothesize that decreasing circulating levels of nutrients including arginine, methionine, and glycine will have anti-tumor activity.

抽象的葡萄糖的快速发酵（“ Warburg效应”）是分配的第一个分子特征癌症。近年来，人们对肿瘤细胞代谢能力的兴趣激增，包括上调的合成代谢，氧化还原防御和替代营养获取途径，例如大型细胞增多症和自噬。这些细胞功能在代谢上起着至关重要的作用最终取决于宿主提供的循环营养素。肿瘤产生的程度能量和生物质构建块来自一些首选的循环营养素，例如葡萄糖，摄取但是，潜水员的营养使自己的生物合成工作最小化，但仍然了解不足。例如，许多肿瘤上调连续生物合成。同时，肿瘤生长对饮食系列敏感进气。哪个贡献更多的是肿瘤中合成的饮食或丝氨酸的丝氨酸？尽管已经做出了大量努力来了解肿瘤细胞中必需的代谢途径，但了解肿瘤对宿主代谢的依赖性相对较少的努力。我们有令人惊讶地观察到，肿瘤循环营养素的消费与培养的癌细胞。我们还令人惊讶地观察到宿主自噬对维持循环营养物质和植入肿瘤的生长完好无损的）。这些发现突出了宿主代谢过程影响肿瘤生长的潜力。什么是肿瘤的关键循环营养素？自噬缺陷如何改变宿主代谢？哪个关键变化会损害肿瘤的生长吗？更广泛地，肿瘤如何依赖宿主代谢被热探索？为了解决这些问题，我们将采用最先进的同位素对肺癌和黑色素瘤鼠肿瘤模型的示踪技术。具体来说，我们将解决角色 K-Ras肺癌小鼠模型以及B-RAF肺癌和黑色素瘤中宿主代谢的宿主代谢：目标1：确定循环营养素和内部肿瘤代谢途径的贡献癌症和黑色素瘤生长。我们假设这一点，而不是使用葡萄糖和谷氨酰胺作为它们原发性底物，体内肿瘤消耗了循环营养素的多样性，包括氨基酸，脂肪和裂缝，从而最大程度地减少生物合成需求并增强代谢鲁棒性。目标2：确定肿瘤对宿主自噬的基础机制。我们假设需要宿主自噬来维持循环养分以支持肿瘤生长。目标3：评估调节循环代谢物的治疗潜力。我们假设这一点循环水平降低包括精氨酸，甲基苯氨酸和甘氨酸在内的循环水平将具有抗肿瘤活动。