Dysplastic Stem Cell Plasticity Functions as a Driving Force for Neoplastic Transformation of Precancerous Gastric Mucosa

Jimin Min, Changqing Zhang, R. Jarrett Bliton, Brianna Caldwell, Leah Caplan, Kimberly S. Presentation, Do Joong Park, Seong Ho Kong, Hye Seung Lee, M. Kay Washington, Woo Ho Kim, Ken S. Lau, Scott T. Magness, Hyuk Joon Lee, Han Kwang Yang, James R. Goldenring, Eunyoung Choi

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Pages (from-to)875-890
Number of pages16
JournalGastroenterology
Volume163
Issue number4
DOIs
StatePublished - Oct 2022

Keywords

  • CK1α
  • Dysplasia
  • Dysplastic Stem Cells
  • Gastric Carcinogenesis
  • Kras
  • Pyrvinium

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