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Nat Commun. 2019 Dec 5;10(1):5549. doi: 10.1038/s41467-019-13479-6.

Heterogeneity and dynamics of active Kras-induced dysplastic lineages from mouse corpus stomach.

Author information

1
Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
2
Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
3
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
4
Cell Imaging Share Resource, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
5
Institute of Pathogen Biology, School of Basic Medical Sciences, Shandong University, Jinan, China.
6
Center for GI Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
7
UNC Departments of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
8
University of North Carolina Chapel Hill/ North Carolina State University joint Departments of Biomedical Engineering, Chapel Hill, NC, 27599, USA.
9
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
10
Nashville VA Medical Center, Nashville, TN, 37232, USA.
11
Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. eunyoung.choi@vumc.org.
12
Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. eunyoung.choi@vumc.org.

Abstract

Dysplasia is considered a key transition state between pre-cancer and cancer in gastric carcinogenesis. However, the cellular or phenotypic heterogeneity and mechanisms of dysplasia progression have not been elucidated. We have established metaplastic and dysplastic organoid lines, derived from Mist1-Kras(G12D) mouse stomach corpus and studied distinct cellular behaviors and characteristics of metaplastic and dysplastic organoids. We also examined functional roles for Kras activation in dysplasia progression using Selumetinib, a MEK inhibitor, which is a downstream mediator of Kras signaling. Here, we report that dysplastic organoids die or show altered cellular behaviors and diminished aggressive behavior in response to MEK inhibition. However, the organoids surviving after MEK inhibition maintain cellular heterogeneity. Two dysplastic stem cell (DSC) populations are also identified in dysplastic cells, which exhibited different clonogenic potentials. Therefore, Kras activation controls cellular dynamics and progression to dysplasia, and DSCs might contribute to cellular heterogeneity in dysplastic cell lineages.

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