Abstract 5165: ADAM17: a common effector for RAS and MET-driven transformation of primary keratinocytes

Abstract

Abstract The purpose of the current study is to determine the contribution of the metalloproteinase ADAM17 (a disintegrin and metalloprotease 17) to the transformation driven by activated MET or oncogenic RAS in primary keratinocytes. Transgenic keratinocytes overexpressing HGF (MT-HGF) to activate MET and keratinocytes transduced with an oncogenic RAS share identical phenotypic and biochemical features of transformation and produce squamous tumors in vivo. In both keratinocyte populations, these common features arise from autocrine activation of EGFR through elevated expression and release of EGFR ligands. Amphiregulin (AREG) blockade in MT-HGF keratinocytes decreases MET-mediated EGFR transactivation. Inhibition of EGFR ablates the initiated signature of MT-HGF keratinocytes in vitro and causes regression of tumors from MT-HGF keratinocytes tranplanted in vivo. Deletion or knock-down of ADAM17 decreases EGFR activation in both RAS and MT-HGF keratinocytes and reverses the transformation associated gene signature in RAS keratinocytes. Using AREG release as an indicator of ADAM17 activity, we determined that knock-down of either the SRC kinase or inactive Rhomboid 2 (iRhom2) reduces the ability of keratinocytes to release AREG upon HGF stimulation. Collectively our data suggest that MET-mediated transformation of keratinocytes occurs through EGFR transactivation and that ADAM17 is a necessary effector for RAS and MET-driven transformation. Citation Format: Christophe Cataisson, Mary Klosterman, Kelly Shibuya, Glenn Merlino, Stuart H. Yuspa. ADAM17: a common effector for RAS and MET-driven transformation of primary keratinocytes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5165.