Abstract 2689: First MACC1 transgenic mice demonstrate tumor progression via the newly discovered MACC1/Nanog/Oct4 axis

Abstract

Abstract We have previously identified the gene Metastasis-Associated in Colon Cancer 1 (MACC1). MACC1 acts a strong prognostic biomarker for colorectal cancer metastasis and patient survival. Meanwhile, MACC1 has been established as a biomarker for tumor progression, metastasis and patient survival for a broad variety of solid cancer types. Here, we report for the first time the generation of transgenic mouse models for MACC1. We generated mice with transgenic overexpression of MACC1 in the intestine driven by the villin promoter (vil-MACC1) and crossed them with ApcMin mice (vil-MACC1/ApcMin). vil-MACC1/ApcMin mice significantly increased the total number of tumors (P = 0.0056). This was particularly apparent in large sized tumors (≥ 3 mm diameter; P = 0.0024). A detailed histopathological analysis of these lesions demonstrated that the tumors from the vil-MACC1/ApcMin mice had a more invasive phenotype together with an accelerated adenoma-carcinoma-sequence. Consequently, vil-MACC1/ApcMin mice showed a significantly reduced survival time as compared to ApcMin mice (P = 0.03). Molecular analysis revealed an increased Wnt and pluripotency signaling in the tumors of vil-MACC1/ApcMin mice. Specifically, we observed a prominent upregulation of the pluripotency markers Oct4 and Nanog in these tumors as compared to ApcMin controls. Finally, we could also validate that Oct4 and Nanog are regulated by MACC1 in vitro, and strongly correlate with MACC1 levels in a cohort of 60 tumors of colorectal cancer patients (r = 0.7005 and r = 0.6808, respectively; P > 0.0001 and P > 0.0002, respectively). Taken together, we provide first evidence that MACC1-induced tumor progression acts, at least in part, via the newly discovered MACC1/Nanog/Oct4 axis. The evidence is accumulated from experiments in cell culture, MACC1 transgenic animals as well as colorectal cancer patients. This is the first time that the function of MACC1 is linked to pathways crucial in cancer stem cells. Based on the hypothesis that cancer stem cells are the main engine behind tumor progression and metastasis, these findings might have important therapeutic implications. Specifically, MACC1's relevance as a biomarker might further be augmented by focusing on its expression in cancer stem cells. Furthermore, the connection of MACC1 with Oct4 and Nanog might offer novel options for therapeutic intervention to restrict tumor progression. Citation Format: Clara Lemos, Markus S. Hardt, Manisha Juneja, Cynthia Voss, Susann Förster, Boris Jerchow, Wolfram Haider, Hendrik Bläker, Ulrike S. Stein. First MACC1 transgenic mice demonstrate tumor progression via the newly discovered MACC1/Nanog/Oct4 axis. [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 2689.