Abstract 1064: The combined activation of MET signaling and PKCα is sufficient to induce tumors in mouse skin.

Abstract

Abstract Aberrant activation of MET signaling has been identified in multiple cancers but its relation to cancer-associated inflammation has not been explored. To address this issue in the context of skin carcinogenesis, a double transgenic mouse model (MT1-HGF/ K5-PKCα or DT) was generated. K5-PKCα mice that overexpress PKCα in basal keratinocytes develop a strong neutrophilic cutaneous inflammatory response upon topical TPA (12-tetradecanoylphorbol-13-acetate) application. These mice were crossed with MT1-HGF mice that overexpress HGF under a metallothionein promoter to create MT1-HGF/ K5-PKCα double transgenic (DT) mice and their respective controls. We observed that DT animals were very sensitive to squamous carcinogenesis. Using a low promoting dose of TPA that primarily activates PKCα in K5-PKCα or DT mice yielded an average of 6 tumors per mouse in the DT group; single transgenic K5-PKCα or MT-HGF mice developed an average of 1 tumor while WT developed none at this TPA dose. We hypothesize that in DT mice, keratinocyte-derived HGF synergizes with PKCα to drive tumor promotion and increase tumor growth. Primary keratinocytes derived from MT1-HGF or DT mice display a phenotype reminiscent of EGFR activated cells: increased expression of pro-inflammatory factors, upregulation of Keratin 8 (K8) and downregulation of K1 and K10 mRNAs. Indeed western blot analysis shows that EGFR is transactivated in MT1-HGF and DT keratinocytes and cell proliferation is elevated as well but not in K5-PKCα or WT keratinocytes. The release of CXCL1,a hallmark of RAS transformation, is augmented in RAS-keratinocyte cell culture supernatants with MT1-HGF and DT keratinocytes producing the most in the absence of RAS-transduction. Blockade of EGFR or IL-1 activity can mitigate the HGF-induced RAS-phenotype. K5-PKCα and DT mice exhibit the same acute inflammatory response and regenerative epidermal hyperplasia following low dose TPA treatment. When promoted for 10 weeks with TPA, 100% of DT mice but none of the single transgenic controls developed squamous papillomas in the absence of DMBA-mediated initiation. Our data suggest that the synergistic activity of Met and PKCα can substitute for the lack of RAS mutation during skin carcinogenesis. It remains to be determined if that mechanism could provide an alternate route to transformation in human skin tumors lacking RAS mutations. Citation Format: Christophe Cataisson, Fan Liu, Lisa N. Wright, Anne Zhuang, Glenn Merlino, Stuart H. Yuspa. The combined activation of MET signaling and PKCα is sufficient to induce tumors in mouse skin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1064. doi:10.1158/1538-7445.AM2013-1064