Abstract 335: A genetic mouse model of head-and-neck squamous cell carcinoma using targeted deletion of E-cadherin and TGFβ receptor II.

Abstract

Abstract We previously observed that 70% of esophageal tumors demonstrated coordinated loss of E-cadherin and TGFβRII. When grown in three-dimensional organotypic reconstruct cultures, cells lacking E-cadherin and TGFβRII demonstrate fibroblast-dependent invasion into the underlying matrix. Therefore, we hypothesized that coordinated loss of CDH1 (E-cadherin) and TGFBR2 (TGFβRII) will induce tumorigenesis in vivo. We developed a mouse model targeting CDH1 and TGFBR2 loss in the oral-esophageal epithelium using the Epstein-Barr virus L2 promoter, ED-L2. For spatio-temporal control of CDH1- and TGFBR2 gene expression, we also generated an inducible mouse model using Cre-ERT(tam) under the control of the keratin 14 promoter. Few mouse models focusing on genetic alterations of oral and head-and-neck cancer exist. We show that the loss of E-cadherin and TGFβ receptor II without carcinogen treatment is sufficient to induce invasive HNSCC and forestomach tumors. Double knock-out animals succumb to the disease between 1 and 1.5 years of age and show invasive tumors in the oral cavity and tongue, as well as the forestomach. Advanced tumors metastasize to the lung. The tumors are characterized by Ki67-positive and p63-positive staining and show disruption of adherens junctions with loss of β-catenin and mislocalisation of p120 to the cytoplasm. Additional genetic modifications frequently described for HNSCC are the upregulation of c-myc and cyclin D1. We could show that the oral mouse tumors are positive for these markers allowing us to conclude that this animal model recapitulates HNSCC at the pathologic and molecular levels. Furthermore, the forestomach is an extension of the squamous epithelium of the esophagus in the mouse. Known genetic alterations causing esophageal squamous cancer are amplification of EGFR, cyclin D1 and mutations in p53 in addition to the loss of E-cadherin and TGFβRII. The analysis of the forestomach tumors recapitulates these events in the mouse model as a result of CDH1 and TGFBR2 loss. This tumor model will provide us with a unique tool for testing therapeutic approaches. Citation Format: Thomas Andl, Gregoire F. Le Bras, Nicole F. Richards, Gillian L. Allison, M. Kay Washington, R. Katie Lee, Claudia D. Andl. A genetic mouse model of head-and-neck squamous cell carcinoma using targeted deletion of E-cadherin and TGFβ receptor II. [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 335. doi:10.1158/1538-7445.AM2013-335