Nutrient Regulation of Cancer Cell Growth

总结 肾细胞癌（RCC）是最常见的肾癌类型，尽管治疗进展， 仍然很高。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形式的肾脏肿瘤发生和进展的共同特征。 癌症，并代表了RCC中的靶向脆弱性。我们的初步结果表明，RCC和其他 癌症依赖于氨基酸天冬酰胺的肿瘤mTORC 1活性和生长，以及消除肿瘤的方法 天冬酰胺水平损害癌细胞增殖并阻断癌生长。癌症通过以下途径获得天冬酰胺 两种主要途径：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，同时减少肿瘤天冬酰胺 消耗和生物合成阻断小鼠中肺癌、乳腺癌和胰腺癌的生长。肿瘤天冬酰胺 可以使用水解血清天冬酰胺的L-天冬酰胺酶（ASNase）或饮食 天冬酰胺限制，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，其通过抑制电子传递链（ETC）的复合物I， 天冬氨酸的产生，天冬酰胺的ASNS生物合成的专性底物。在这份更新提案中， 我们将研究肾癌的天冬酰胺依赖性，以确定天冬酰胺缺乏是否可以 广泛应用于治疗各种亚型的RCC患者。我们还将确定 天冬酰胺在癌细胞中被感知以影响mTORC 1活性，以及天冬酰胺缺失是否影响 RCC肿瘤微环境中的免疫细胞活化。

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.