Dysplastic Stem Cell Plasticity Functions as a Driving Force for Neoplastic Transformation of Precancerous Gastric Mucosa
Year: 2022
Type: article
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, CD44v6 neg /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.
Source: Gastroenterology
Language: English
Topic: Cancer Cells and Metastasis
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,200
Funders: U.S. Department of Defense, U.S. Department of Veterans Affairs, Vanderbilt-Ingram Cancer Center, National Institutes of Health, Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina at Chapel Hill, DOD Peer Reviewed Cancer Research Program
Awards: G1331061530, G1764958080, G1948135505, G2006259475, G2075301929, G2303287163, G3161482043, G3269002440, G3738690458, G402423035, SPORE in GI Cancer, G5614773401, G5810341914, G706055121, G725763919, G7374619306, G7922862772, Induction and Evolution of Metaplasia in the Stomach, Molecular and Cellular Basis for Digestive Diseases, Center for Gastrointestinal Biology and Disease, Drivers of gastric pre-neoplasia
OpenAlex ID: W4282971685