Nutrient Regulation of Cancer Cell Growth

摘要 肾细胞癌 (RCC) 是最常见的肾癌类型，尽管治疗取得了进展，但死亡率 仍然处于高位。虽然有十几种 RCC 亚型具有不同的基因组驱动因素，但代谢 重编程是大多数主要肾脏形式肿瘤发生和进展的共同特征 癌症，代表了 RCC 中的一个可针对的脆弱性。我们的初步结果表明，农村信用社和其他 癌症依赖氨基酸天冬酰胺来促进肿瘤 mTORC1 活性和生长，以及消除肿瘤的方法 天冬酰胺水平会损害癌细胞增殖并阻止癌症生长。癌症通过以下途径获取天冬酰胺 两条主要途径：1）从环境中消耗，2）通过天冬酰胺从天冬氨酸生物合成 合成酶（ASNS）。在过去的 5 年里，我们发现天冬酰胺可以同时减少肿瘤 消耗和生物合成可阻止小鼠肺癌、乳腺癌和胰腺癌的生长。肿瘤天冬酰胺 可以使用 L-天冬酰胺酶 (ASNase) 来确定消耗量，该酶可水解血清天冬酰胺，或者通过膳食 天冬酰胺限制，可降低血清天冬酰胺水平。肿瘤天冬酰胺生物合成可靶向 使用二甲双胍，通过抑制电子传递链 (ETC) 的复合物 I，减少癌细胞 天冬氨酸的生产，天冬氨酸是 ASNS 生物合成天冬酰胺的必需底物。在这次更新提案中， 我们将研究肾癌天冬酰胺依赖性，以确定天冬酰胺消耗是否可以 广泛应用于治疗各种亚型肾细胞癌患者。我们还将确定机制 癌细胞中检测到天冬酰胺会影响 mTORC1 活性以及天冬酰胺消耗是否会影响 RCC 肿瘤微环境中的免疫细胞激活。

SUMMARY Renal cell cancer (RCC) is the most common type of kidney cancer, and despite therapeutic advances, mortality remains high. While there are over a dozen RCC subtypes with different genomic drivers, metabolic reprogramming is a shared feature of tumorigenesis and progression across most of the major forms of kidney cancer and represents a targetable vulnerability in RCC. Our preliminary results show that RCCs and other cancers rely on the amino acid asparagine for tumor mTORC1 activity and growth, and methods to deplete tumor asparagine levels impair cancer cell proliferation and block cancer growth. Cancers acquire asparagine through two main routes: 1) consumption from the environment, and 2) biosynthesis from aspartate via asparagine synthetase (ASNS). Over the last 5 years, we found that simultaneous reduction of tumor asparagine consumption and biosynthesis blocks growth of lung, breast, and pancreas cancers in mice. Tumor asparagine consumption can be targeted using L-Asparaginase (ASNase), which hydrolyzes serum asparagine, or dietary asparagine restriction, which reduces serum asparagine levels. Tumor asparagine biosynthesis can be targeted using metformin, which through inhibiting complex I of the electron transport chain (ETC), reduces cancer cell production of aspartate, an obligate substrate for ASNS biosynthesis of asparagine. In this renewal proposal, we will investigate kidney cancer asparagine dependency to determine whether asparagine depletion can be broadly applied to treat patients with various subtypes of RCC. We will also determine the mechanism by which asparagine is sensed in cancer cells to impact mTORC1 activity and whether asparagine depletion impacts immune cell activation within the RCC tumor microenvironment.