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 仍然居高不下。虽然有十几种肾癌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形式肾脏肿瘤发生和发展的共同特征 癌症，代表着RCC的一个可靶向的脆弱性。我们的初步结果显示，农村信用社和其他 肿瘤依赖于氨基酸天冬酰胺对肿瘤mTORC1的活性和生长，以及消耗肿瘤的方法 天冬酰胺水平会损害癌细胞的增殖，阻碍癌症的生长。癌症通过以下途径获得天冬酰胺 两条主要途径：1)从环境中消耗，2)天冬氨酸通过天冬酰胺生物合成 合成酶(ASNS)。在过去的5年里，我们发现同时减少肿瘤天冬酰胺 消耗和生物合成阻止了小鼠肺癌、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(天冬酰胺酶)或饮食中的天冬酰胺酶来确定消费的目标 限制天冬酰胺，降低血清天冬酰胺水平。肿瘤天冬酰胺的生物合成可以被靶向 使用二甲双胍，它通过抑制电子传输链(ETC)的复合体I，减少癌细胞 天冬氨酸的生产，天冬氨酸是天冬氨酸生物合成的必需底物。在这份续签提案中， 我们将调查肾癌对天冬酰胺的依赖情况，以确定天冬酰胺耗竭是否可以 广泛应用于治疗各种亚型肾细胞癌患者。我们还将确定通过什么机制 天冬酰胺在癌细胞中被检测到影响mTORC1的活性，以及天冬酰胺的缺乏是否会影响 肾细胞癌微环境中免疫细胞的激活。

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.