title: Invasive mouse gastric adenocarcinomas arising from Lgr5+ stem cells are dependent on crosstalk between the Hedgehog/GLI2 and mTOR pathways.
abstract: 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.
authors: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors: Li-Jyun
authors: LJ
authors: Syu
authors: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors: Xinyi
authors: X
authors: Zhao
authors: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors: Yaqing
authors: Y
authors: Zhang
authors: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors: Marina
authors: M
authors: Grachtchouk
authors: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
authors: Elise
authors: E
authors: Demitrack
authors: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors: Alexandre
authors: A
authors: Ermilov
authors: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors: Dawn M
authors: DM
authors: Wilbert
authors: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors: Xinlei
authors: X
authors: Zheng
authors: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors: Ashley
authors: A
authors: Kaatz
authors: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors: Joel K
authors: JK
authors: Greenson
authors: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
authors: Deborah L
authors: DL
authors: Gumucio
authors: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.|Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA.
authors: Juanita L
authors: JL
authors: Merchant
authors: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors: Marina Pasca
authors: MP
authors: di Magliano
authors: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.|Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA.
authors: Linda C
authors: LC
authors: Samuelson
authors: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.|Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
authors: Andrzej A
authors: AA
authors: Dlugosz
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D053823:Hedgehog Proteins / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000473:pathology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000627:therapeutic use; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D013274:Stomach Neoplasms / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000075746:Zinc Finger Protein Gli2; D051176:beta Catenin / Q000378:metabolism
chemical_list: C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D000075746:Zinc Finger Protein Gli2; D051176:beta Catenin; C546843:mTOR protein, mouse; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: GLI2; Lgr5; gastric cancer; mTOR; stem cells