Abstract 2291: Snai1 accelerates Kras driven lung tumorigenesis by overcoming oncogene-induced senescence
Authors: Kekoa Taparra, Hailun Wang, Katriana Nugent, Russell Williams, Reem Malek, Jessica Cades, Dean Felsher, Phuoc Tran
Journal: Cancer Research (2015)

Abstract Lung cancer is the deadliest cancer worldwide with the majority of cases being non-small cell lung cancer (NSCLC). The most common oncogenic driver in NSCLC patients is mutant KRAS. Mutant KRAS driven proliferation is abated by the failsafe mechanism of oncogene-induced senescence (OIS) in primary cell lines. TWIST1, an inducer of epitheilal-mesenchymal transition (EMT), can overcome OIS, rescuing proliferative capacity of mutant KRAS in primary cells. SNAI1 is another classical EMT master regulator critical in development and is aberrantly expressed in breast, liver, colon, and lung cancers. SNAI1 expression correlates with tumor recurrence and poor patient prognosis. However, there is no evidence for the role of SNAI1 in autochthonous lung tumorigenesis in vivo. To study SNAI1 in lung tumorigenesis, we developed a novel inducible SNAI1 transgenic mouse model. The Club Cell Secretory Protein (CCSP)-rtTA (C) lung tissue specific driver founder line was crossed with a bidirectional transgenic founder line, SNAI1-6SA-tetO7-luc (S), to generate CS mice. CS mice were crossed with inducible oncogenic driver tetO7-KrasG12D (R) mice to produce the triple transgenic, CRS. Inducible SNAI1 expression was confirmed by multiple methods in this novel mouse model. Interestingly, a Kaplan-Meier curve analysis showed that SNAI1 overexpression accelerated KrasG12D-driven lung tumorigenesis compared to KrasG12D alone in vivo. SNAI1 reduced median KrasG12D tumor latency from 31 to 15 weeks of doxycycline (DOX) induction and SNAI1 driven CRS mice developed more aggressive lung adenocarcinomas than the CR model. Upon DOX removal lung tumor moribund mice demonstrated complete radiographic tumor regression, demonstrating tumor maintenance in CRS mice is dependent on KrasG12D and/or SNAI1. To begin to elucidate how SNAI1 may accelerate lung tumorigenesis, inducible SNAI1 mouse embryonic fibroblasts (MEFs) were generated. These MEFs were used to assess if SNAI1 could suppress OIS and promote HRASG12V driven proliferation. While uninduced MEFs senesced within days of HRASG12V infection, DOX induced SNAI1 MEFs had a reduced number of senescence associated Beta-gal positive cells. Furthermore, cellular proliferation showed stagnancy in uninduced HRASG12V infected MEFs, while induced SNAI1 MEFs maintained proliferative capacity. Studies investigating SNAI1-directed epigenetic and transcriptional regulation of metabolic gene targets implicated in circumventing OIS in this model are underway. Overall, these studies demonstrate that SNAI1 may overcome OIS in mutant RAS driven cells to facilitate cellular proliferation and tumorigenesis. Citation Format: Kekoa Taparra, Hailun Wang, Katriana Nugent, Russell Williams, Reem Malek, Jessica Cades, Dean Felsher, Phuoc Tran. Snai1 accelerates Kras driven lung tumorigenesis by overcoming oncogene-induced senescence. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2291. doi:10.1158/1538-7445.AM2015-2291