Invasive mouse gastric adenocarcinomas arising from Lgr5+ stem cells are dependent on crosstalk between the Hedgehog/GLI2 and mTOR pathways
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Li-Jyun Syu1, Xinyi Zhao1, Yaqing Zhang2, Marina Grachtchouk1, Elise Demitrack3, Alexandre Ermilov1, Dawn M. Wilbert1, Xinlei Zheng1, Ashley Kaatz1, Joel K. Greenson4, Deborah L. Gumucio5, Juanita L. Merchant3,6, Marina Pasca di Magliano2, Linda C. Samuelson3,6 and Andrzej A. Dlugosz1,5
1 Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
2 Department of Surgery, University of Michigan, Ann Arbor, MI, USA
3 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
4 Department of Pathology, University of Michigan, Ann Arbor, MI, USA
5 Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
6 Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
Andrzej Dlugosz, email:
Keywords: gastric cancer, stem cells, Lgr5, GLI2, mTOR
Received: October 10, 2015 Accepted: January 24, 2016 Published: February 03, 2016
Gastric adenocarcinoma is the third most common cause of cancer-related death worldwide. Here we report a novel, highly-penetrant mouse model of invasive gastric cancer arising from deregulated Hedgehog/Gli2 signaling targeted to Lgr5-expressing stem cells in adult stomach. Tumor development progressed rapidly: three weeks after inducing the Hh pathway oncogene GLI2A, 65% of mice harbored in situ gastric cancer, and an additional 23% of mice had locally invasive tumors. Advanced mouse gastric tumors had multiple features in common with human gastric adenocarcinomas, including characteristic histological changes, expression of RNA and protein markers, and the presence of major inflammatory and stromal cell populations. A subset of tumor cells underwent epithelial-mesenchymal transition, likely mediated by focal activation of canonical Wnt signaling and Snail1 induction. Strikingly, mTOR pathway activation, based on pS6 expression, was robustly activated in mouse gastric adenocarcinomas from the earliest stages of tumor development, and treatment with rapamycin impaired tumor growth. GLI2A-expressing epithelial cells were detected transiently in intestine, which also contains Lgr5+ stem cells, but they did not give rise to epithelial tumors in this organ. These findings establish that deregulated activation of Hedgehog/Gli2 signaling in Lgr5-expressing stem cells is sufficient to drive gastric adenocarcinoma development in mice, identify a critical requirement for mTOR signaling in the pathogenesis of these tumors, and underscore the importance of tissue context in defining stem cell responsiveness to oncogenic stimuli.
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