Abstract 5188: Lrig1, a cell surface negative regulator of ErbB1-4, marks both proliferative and quiescent intestinal stem cells and acts as a tumor suppressor

Abstract

Abstract Whether proliferative and quiescent intestinal stem cells coexist in normal and cancerous tissue is controversial. Due to heightened transcript expression in the intestinal epithelial stem cell compartment, detection in quiescent hair follicle stem cells and frequent loss in breast cancer, we hypothesized that Leucine-rich repeats and immunoglobulin-like domain protein 1 (Lrig1) would mark a novel population of intestinal stem cells and may be important for intestinal homeostasis and in cancer. To study this, we generated Lrig1-CreERT2/+; R26R-LacZ mice to study the role of Lrig1. One day after Lrig1-CreERT2/+; R26R-LacZ mice received a single injection of tamoxifen, 1-2 cells were labeled in the progenitor zone. Three months after injection, 10% of colonic crypts were entirely labeled and 8% of crypts contained singly labeled, non-proliferative, Lgr5-negative cells at the crypt-base. In a regenerative response to gut injury, these singly labeled cells proliferated and gave rise to clusters of labeled daughter cells, demonstrating the ability of these quiescent stem cells to become activated. Loss of Lrig1 resulted in heightened expression of ErbB1-3 in the normal intestine, duodenal adenomas and carcinoma, supporting a functional role for Lrig1 in the maintenance of intestinal epithelial homeostasis and its ability to act as a tumor suppressor. In addition, driving stochastic loss of Apc in Lrig1-expressing cells results in multiple, large distal colonic tumors and less frequent, smaller intestinal tumors, which are common features of human familial polyposis. In summary, we show that Lrig1, a cell surface negative regulator of ErbB1-4, marks both proliferative and quiescent intestinal stem cells and acts as a tumor suppressor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5188. doi:10.1158/1538-7445.AM2011-5188