Tumor Cell Dependence on Host Metabolism

肿瘤细胞对宿主代谢的依赖性

• 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
• 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

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.

摘要 葡萄糖快速发酵为乳酸(“沃堡效应”)是第一个被指认的分子特征。 致癌。近年来，人们对肿瘤细胞的代谢能力产生了极大的兴趣， 包括上调合成代谢、氧化还原防御和营养获取的替代途径，如 巨噬细胞增多症和自噬。虽然这些细胞能力在新陈代谢方面起着关键作用，但肿瘤 最终取决于宿主提供的循环营养。肿瘤产生的程度 能量和生物量由葡萄糖等几种首选循环营养物质构成，而不是吸收 然而，对于减少自身生物合成工作的各种营养物质，人们仍然知之甚少。例如, 许多肿瘤上调丝氨酸的生物合成。同时，肿瘤的生长对饮食中的丝氨酸很敏感。 入口处。从饮食中获得的循环丝氨酸和在肿瘤中合成的丝氨酸，哪一种贡献更大？ 虽然已经做出了大量的努力来了解肿瘤细胞内的基本代谢途径， 在了解肿瘤对宿主新陈代谢的依赖方面，相对较少的努力。我们有 令人惊讶地观察到，肿瘤对循环营养的消耗与 培养的癌细胞。我们还出人意料地观察到宿主自噬对于 维持循环营养和植入性肿瘤的生长(自噬仍然存在 完好无损)。这些发现突出了宿主代谢过程影响肿瘤生长的潜力。何谓 肿瘤的关键循环营养物质？自噬缺陷是如何改变宿主代谢的？哪一个 是损害肿瘤生长的关键变化吗？更广泛地说，肿瘤是如何依赖宿主的 新陈代谢可用于治疗吗？为了解决这些问题，我们将使用最先进的同位素 肺癌和黑色素瘤小鼠肿瘤模型的示踪技术。具体地说，我们将解决 K-RAS肺癌、B-Raf肺癌和黑色素瘤小鼠模型的宿主代谢： 目的1：确定循环营养素和肿瘤内部代谢途径对肺的贡献 癌症和黑色素瘤的生长。我们假设，与其使用葡萄糖和谷氨酰胺作为他们的 主要的底物，体内的肿瘤消耗各种各样的循环营养物质，包括氨基酸， 脂肪和乳酸，从而将生物合成需求降至最低，并增强新陈代谢的稳定性。 目的2：确定肿瘤依赖宿主自噬的机制。我们假设 宿主自噬是维持循环营养以支持肿瘤生长所必需的。 目的3：评估调节循环代谢产物的治疗潜力。我们假设 降低循环中的营养水平，包括精氨酸、蛋氨酸和甘氨酸，将具有抗肿瘤作用。 活动。