Tumor Cell Dependence on Host Metabolism

摘要 葡萄糖快速发酵成乳酸（“瓦尔堡效应”）是第一个被指定的分子特征 到癌症近年来，人们对肿瘤细胞的代谢能力产生了极大的兴趣， 包括上调的抗氧化剂、氧化还原防御和营养获取的替代途径， 巨胞饮和自噬。虽然这些细胞能力在代谢方面发挥着关键作用，但肿瘤 最终取决于宿主提供的循环营养。肿瘤产生的程度 能量和生物量的构建块从一些优选的循环营养素，如葡萄糖，与摄取 然而，人们对各种营养素如何最大限度地减少其自身的生物合成工作仍然知之甚少。比如说， 许多肿瘤上调丝氨酸生物合成。同时，肿瘤生长对膳食丝氨酸敏感 摄入哪一种贡献更多的循环丝氨酸--来自饮食还是肿瘤中合成的丝氨酸？ 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， 相对而言，很少有人致力于了解肿瘤对宿主代谢的依赖性。我们有 令人惊讶地观察到，肿瘤对循环营养物的消耗与 即培养的癌细胞。我们还惊奇地观察到，宿主自噬对于 维持循环营养和用于植入肿瘤的生长（其中自噬仍然存在 完整）。这些发现强调了宿主代谢过程影响肿瘤生长的潜力。是什么 肿瘤的关键循环营养物质自噬缺陷如何改变宿主的代谢？这 是阻碍肿瘤生长的关键变化吗更广泛地说，肿瘤如何依赖于宿主 新陈代谢可以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 示踪技术用于肺癌和黑色素瘤的鼠肿瘤模型。具体而言，我们将讨论 K-Ras肺癌、B-Raf肺癌和黑色素瘤小鼠模型中的宿主代谢： 目的1：确定循环营养物质和肿瘤内部代谢途径对肺的贡献 癌症和黑色素瘤生长。我们假设，与其使用葡萄糖和谷氨酰胺作为它们的 作为主要底物，体内肿瘤消耗多种多样的循环营养物，包括氨基酸， 脂肪和乳酸盐，从而使生物合成需求最小化并增强代谢稳健性。 目的2：探讨肿瘤对宿主自噬依赖性的机制。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：评估调节循环代谢物的治疗潜力。我们假设 降低包括精氨酸、甲硫氨酸和甘氨酸在内的营养物质的循环水平将具有抗肿瘤作用。 活动

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.