Jimin Min1, Changqing Zhang1, R Jarrett Bliton2, Brianna Caldwell1, Leah Caplan3, Kimberly S Presentation1, Do-Joong Park4, Seong-Ho Kong4, Hye Seung Lee5, M Kay Washington6, Woo-Ho Kim5, Ken S Lau7, Scott T Magness2, Hyuk-Joon Lee4, Han-Kwang Yang4, James R Goldenring8, Eunyoung Choi9. 1. Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee. 2. Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina at Chapel Hill, Raleigh, North Carolina; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 3. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. 4. Department of Surgery, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. 5. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Department of Pathology, Seoul National University College of Medicine, Seoul, Korea. 6. Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee. 7. Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. 8. Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Nashville VA Medical Center, Nashville, Tennessee. 9. Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. Electronic address: eunyoung.choi@vumc.org.
Abstract
BACKGROUND & AIMS: Dysplasia carries a high risk of cancer development; however, the cellular mechanisms for dysplasia evolution to cancer are obscure. We have previously identified 2 putative dysplastic stem cell (DSC) populations, CD44v6neg/CD133+/CD166+ (double positive [DP]) and CD44v6+/CD133+/CD166+ (triple positive [TP]), which may contribute to cellular heterogeneity of gastric dysplasia. Here, we investigated functional roles and cell plasticity of noncancerous Trop2+/CD133+/CD166+ DSCs initially developed in the transition from precancerous metaplasia to dysplasia in the stomach. METHODS: Dysplastic organoids established from active Kras-induced mouse stomachs were used for transcriptome analysis, in vitro differentiation, and in vivo tumorigenicity assessments of DSCs. Cell heterogeneity and genetic alterations during clonal evolution of DSCs were examined by next-generation sequencing. Tissue microarrays were used to identify DSCs in human dysplasia. We additionally evaluated the effect of casein kinase 1 alpha (CK1α) regulation on the DSC activities using both mouse and human dysplastic organoids. RESULTS: We identified a high similarity of molecular profiles between DP- and TP-DSCs, but more dynamic activities of DP-DSCs in differentiation and survival for maintaining dysplastic cell lineages through Wnt ligand-independent CK1α/β-catenin signaling. Xenograft studies demonstrated that the DP-DSCs clonally evolve toward multiple types of gastric adenocarcinomas and promote cancer cell heterogeneity by acquiring additional genetic mutations and recruiting the tumor microenvironment. Last, growth and survival of both mouse and human dysplastic organoids were controlled by targeting CK1α. CONCLUSIONS: These findings indicate that the DSCs are de novo gastric cancer-initiating cells responsible for neoplastic transformation and a promising target for intervention in early induction of gastric cancer.
BACKGROUND & AIMS: Dysplasia carries a high risk of cancer development; however, the cellular mechanisms for dysplasia evolution to cancer are obscure. We have previously identified 2 putative dysplastic stem cell (DSC) populations, CD44v6neg/CD133+/CD166+ (double positive [DP]) and CD44v6+/CD133+/CD166+ (triple positive [TP]), which may contribute to cellular heterogeneity of gastric dysplasia. Here, we investigated functional roles and cell plasticity of noncancerous Trop2+/CD133+/CD166+ DSCs initially developed in the transition from precancerous metaplasia to dysplasia in the stomach. METHODS: Dysplastic organoids established from active Kras-induced mouse stomachs were used for transcriptome analysis, in vitro differentiation, and in vivo tumorigenicity assessments of DSCs. Cell heterogeneity and genetic alterations during clonal evolution of DSCs were examined by next-generation sequencing. Tissue microarrays were used to identify DSCs in human dysplasia. We additionally evaluated the effect of casein kinase 1 alpha (CK1α) regulation on the DSC activities using both mouse and human dysplastic organoids. RESULTS: We identified a high similarity of molecular profiles between DP- and TP-DSCs, but more dynamic activities of DP-DSCs in differentiation and survival for maintaining dysplastic cell lineages through Wnt ligand-independent CK1α/β-catenin signaling. Xenograft studies demonstrated that the DP-DSCs clonally evolve toward multiple types of gastric adenocarcinomas and promote cancer cell heterogeneity by acquiring additional genetic mutations and recruiting the tumor microenvironment. Last, growth and survival of both mouse and human dysplastic organoids were controlled by targeting CK1α. CONCLUSIONS: These findings indicate that the DSCs are de novo gastric cancer-initiating cells responsible for neoplastic transformation and a promising target for intervention in early induction of gastric cancer.
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Authors: Su-Hyung Lee; Bogun Jang; Jimin Min; Ela W Contreras-Panta; Kimberly S Presentation; Alberto G Delgado; M Blanca Piazuelo; Eunyoung Choi; James R Goldenring Journal: Cell Mol Gastroenterol Hepatol Date: 2021-08-26