Abstract 1229: Deciphering molecular mechanisms of metastasis in renal cell carcinoma

Abstract Across human cancer, tumors that are high grade, poorly differentiated, and have undergone epithelial-to-mesenchymal transition (EMT) carry a worse prognosis with a high likelihood of metastasizing to distant organs. Despite significant research efforts, metastatic cancers and relapse remain the primary cause of cancer related deaths. In renal cell carcinoma (RCC), metastasis is present in one-third of patients at the time of diagnosis, and one-third of patients who initially present with locally advanced disease eventually develop local or distant recurrence following resection of the primary tumor, highlighting the need for new RCC therapies and further insight into the metastatic process. Using patient biopsies, immunohistochemistry, sequencing, and available clinical data in a cohort of RCC patients, we found that patients with more epithelial tumors have a significantly lower risk of recurrence. Unexpectedly, patients whose tumors had a mesenchymal protein signature had significantly increased infiltration of macrophages within their tumors. Additionally, increased macrophages in the primary tumor were significantly associated with a higher tumor stage at diagnosis and worse overall survival, suggesting that macrophages may play an important role in EMT in ccRCC. Furthermore, whole exome sequencing revealed that patients with increased macrophage infiltrate had a mutational loss of SETD2, a histone methyltransferase. Additionally, macrophages and EMT are also correlated, and tumor cell adhesion is reduced when SETD2 is lost in ccRCC patients. Further studies are needed to determine if SETD2 loss plays a role in the recruitment of macrophages to the tumor and EMT. Further characterization of the gene signatures, metabolic phenotypes, and immune cell infiltrate within these patient samples will lead to a better understanding of metastasis in an oncogene- and tissue-specific manner and thus lead to more efficacious therapies for metastatic patients. Citation Format: Emily Nicole Arner, Melissa M. Wolf, Logan Vlach, Vania J. Sih, Dalton L. Greenwood, Scott Haake, Jeffrey C. Rathmell, Kimryn Rathmell. Deciphering molecular mechanisms of metastasis in renal cell carcinoma [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 1229.