Abstract 4077: Impact of RET/PTC3 oncogene's inflammatory and transformative signaling on tumorigenicity of thyroid and non-thyroid tumorigenic cell lines

Abstract

Abstract Rearranged in transformation/ papillary thyroid carcinoma 3 (RET/PTC3 or RP3), is a unique fusion oncogene, responsible for a benign version of PTC. RP3 has an active inflammatory component leading to the secretion of various pro-inflammatory cytokines, however the role of inflammation in development and progression of PTC has not been clearly defined. Facilitating investigation of this issue is our finding that the transforming and inflammatory signals of RP3 can be functionally separated allowing us to study each in isolation. We generated several RP3 mutants ablated in; 1) transformative signaling due to mutation of a tyrosine residue (RP3Y588Fmutant) which prevents the binding of downstream adaptor proteins 2) inflammatory signaling through mutation of binding sites for TRAF2 and TRAF6. Transformation only RP3 mutants grew tumors in immunodeficient and immunocompetent mice, strengthening our hypothesis that the inflammatory component of RP3 is responsible for the benign nature of PTC. To assess the impact of inflammatory RP3 on the progression of different tumors, various thyroid and non-thyroid tumorigenic cell lines were transduced with MSCV_IRES_GFP_RP3 mutants and sorted for GFP expression. With highly immunogenic MC57G cells (C57BL/6 mice), the transforming only mutants developed tumors whereas wild type RP3 along with inflammatory only RP3 were rejected. Inflammation only RP3 mutant also led to slower tumor growth in Renca cell line (Balb/c) demonstrating the effect to be independent of haplotype. We are currently extending the analysis to PTC lines with BRAF and KRAS mutations, which are usually associated with more aggressive tumor profiles without an inflammatory tumor microenvironment. Our data so far suggest that contrary to the contemporary view, inflammation can retard tumor progression. Thus, the RP3 oncogene might be exploited in this regard. Future experiments aim to further characterize the importance of RP3-driven inflammation in tumor growth through continued in vivo and in vitro studies. Citation Format: Suresh C. Kari, Laurence C. Eisenlohr. Impact of RET/PTC3 oncogene's inflammatory and transformative signaling on tumorigenicity of thyroid and non-thyroid tumorigenic cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4077. doi:10.1158/1538-7445.AM2014-4077