Abstract B004: Serine promotes invasive phenotype through enhanced translation of SNAIL in ccRCC

Abstract

Abstract Background: Metastatic clear cell renal cell carcinoma (ccRCC) is the most common type of renal carcinoma with a median survival rate of about 13 months and is refractory to chemotherapy. ccRCC is fundamentally a metabolic disease characterized by extensive reprogramming in amino acid metabolism. Serine is a nonessential amino acid (NEAA), and the serine biosynthetic pathway has been shown as an essential source of metabolic intermediates in many cancers. Analysis of the TCGA database reveals that ccRCC tumors have reduced levels of PHGDH, the first enzyme in the de novo serine biosynthesis pathway, and makes serine conditionally essential amino acid in these tumors. The role of serine in tumorigenesis is well established; however, its role in promoting invasive phenotype and metastasis is not explored. Methods: To gain insight into the role of nonessential amino acids in proinvaisive phenotypes, we performed wound healing and migration assays in the presence of individual NEAAs. The importance of serine synthesis for promoting invasive phenotype was also assessed by restoring PHGDH in low PHGDH ccRCC. Results: In an unbiased approach, we found that serine is required for the increased migratory and invasive phenotype in ccRCC. We also demonstrate that in low PHGDH ccRCC cells, exogenous serine is to maintain SNAIL expression and the enhanced migratory and invasive phenotype. We also show that serine depletion induces translational inhibition in low PHGDH ccRCC. Conclusion: The role of serine in tumorigenesis and cell proliferation is well established; however, its role in supporting invasive and metastatic phenotypes is previously unknown. Our data highlights a novel role for serine in promoting EMT through enhanced translational maintenance of SNAIL, which may be therapeutically targeted in ccRCC. Citation Format: Suman Karki. Serine promotes invasive phenotype through enhanced translation of SNAIL in ccRCC [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B004.