LAUSR

Tumor cells are known to have increased demand for nutrients to support proliferation. Among the most highly utilized nutrients by tumor cells are nonessential amino acids (NEAAs). While the role of NEAAs in supporting tumor growth is well-established, their role in supporting aggressive phenotypes such as migration and invasion is poorly understood. Yet, the major cause of morbidity from malignancies such as renal cell carcinoma (RCC) is metastasis. Through an unbiased approach, we assayed the role of NEAAs in promoting the migration of RCC cells. We demonstrate that exogenous serine and glutamine are essential and sufficient to support aggressive phenotypes in RCC. Moreover, the availability of both NEAAs is critical for the expression of the proinvasive transcription factor SNAIL. Our data converge on the role of these two NEAAs in supporting the translation of this factor. Perturbations that limit the availability and/or synthesis of either result in translational reprogramming through the integrated stress response (ISR) that leads to loss of SNAIL1 expression and attenuates aggressive phenotypes. Our findings associate nutrient status to the ISR including ER stress. Collectively, our study highlights new insights for NEAA metabolism in supporting aggressive tumor phenotypes and could reveal novel approaches to mitigate metastasis by targeting NEAA availability and/or utilization. Citation Format: Suman Karki, Anirban Kundu, Garret Brinkley, Hyeyoung Nam, Kayla Goliwas, Jessy Deshane, Sunil Sudarshan. Serine promotes aggressive phenotype in renal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3702.