LAUSR

Lung cancer kills more people in the United States than any other malignancy. High mortalities are in part due to the diagnosis at an advanced inoperable stage where the 5-year survival is only 4%. Therefore, improving survival will require increased knowledge of genes that drive the complex mechanisms of lung cancer initiation and progression. Emerging data implicate novel roles for protein arginine methylation in lung cancers. In protein arginine methylation, nitrogen/s of arginine can be post-translationally modified via the addition of a methyl group, catalyzed by a class of enzymes, protein arginine methyl transferases (PRMTs). Based on the computational analysis, tissue staining, and immunoblotting we have identified an increased expression of PRMT6 in lung tumors. To test the biologic relevance of PRMT6 in lung tumor development, we employed an inducible lung-targeted PRMT6 gain-of-function (GOF) mouse model. For the first time, we show that lung-targeted overexpression of PRMT6 results in spontaneous lung tumor development. We also observed a robust increase in lung tumors in the PRMT6 GOF mice in response to urethane, a KRas mutagen, and a prototypical model to study lung tumorigenesis. Excitingly, we detected an increase in the number of tumor-associated macrophages (TAMs) in the PRMT6 GOF mice. Further characterization of the TAMs from the PRMT6 GOF mice revealed that they were M2 polarized with immunosuppressive, angiogenesis-enhancing, and tumor-promoting activities. Taken together, these results demonstrate a novel role for PRMT6 in lung tumor development by way of macrophage M2 polarization. Therefore, defining the complete mechanism of PRMT6-mediated macrophage M2 polarization could lead to the development of novel therapeutic strategies to treat lung cancer. Citation Format: Sreedevi Avasarala, Pei-Ying Wu, Samia Q. Khan, Michelle Van Scoyk, Yanlin Su, Odile David, Vineet Gupta, Mark T. Bedford, Robert A. Winn, Rama Kamesh Bikkavilli. PRMT6 promotes lung tumor growth via the modulation of macrophage M2 polarization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 138.