한빛사 논문
Jimin Min1,2, Changqing Zhang1,2, R. Jarrett Bliton6,7,8, Brianna Caldwell1,2, Leah Caplan3, Kimberly S. Presentation1,2, Do-Joong Park9,11, Seong-Ho Kong9,11, Hye Seung Lee10,11, M. Kay Washington5, Woo-Ho Kim10,11, Ken S. Lau2,3, Scott T. Magness6,7,8, Hyuk-Joon Lee9,11, Han-Kwang Yang9,11, James R. Goldenring1,2,3,4, Eunyoung Choi*1,2,3
1Department of Surgery, 2Epithelial Biology Center, 3Department of Cell and Developmental Biology, 4Nashville VA Medical Center, 5Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA 6Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina at Chapel Hill, Raleigh, North Carolina, 27695, USA 7Department of Cell Biology & Physiology, 8Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA 9Department of Surgery, 10Department of Pathology, 11Cancer Research Institute, Seoul National University College of Medicine, Seoul, 03080, Korea
*Correspondence
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 two putative dysplastic stem cell (DSC) populations, CD44v6neg/CD133+/CD166+ (DP) and CD44v6+/CD133+/CD166+ (TP), which may contribute to cellular heterogeneity of gastric dysplasia. Here, we investigated functional roles and cell plasticity of non-cancerous Trop2+/CD133+/CD166+ DSCs initially developed in the transition from pre-cancerous metaplasia to dysplasia in the stomach.
Methods
Dysplastic organoids established from active Kras-induced mouse stomachs were utilized 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 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 towards multiple types of gastric adenocarcinomas and promote cancer cell heterogeneity by acquiring additional genetic mutations and recruiting the tumor microenvironment. Lastly, 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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