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

Author

Listed:
  • Jimin Min

    (Vanderbilt University School of Medicine
    Vanderbilt University School of Medicine)

  • Paige N. Vega

    (Vanderbilt University School of Medicine
    Vanderbilt University School of Medicine)

  • Amy C. Engevik

    (Vanderbilt University School of Medicine
    Vanderbilt University School of Medicine)

  • Janice A. Williams

    (Vanderbilt University School of Medicine)

  • Qing Yang

    (Vanderbilt University School of Medicine
    Vanderbilt University School of Medicine
    Shandong University)

  • Loraine M. Patterson

    (University of North Carolina at Chapel Hill)

  • Alan J. Simmons

    (Vanderbilt University School of Medicine
    Vanderbilt University School of Medicine)

  • R. Jarrett Bliton

    (University of North Carolina at Chapel Hill)

  • Joshua W. Betts

    (Vanderbilt University School of Medicine)

  • Ken S. Lau

    (Vanderbilt University School of Medicine
    Vanderbilt University School of Medicine)

  • Scott T. Magness

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill
    University of North Carolina Chapel Hill/ North Carolina State University joint Departments of Biomedical Engineering
    University of North Carolina at Chapel Hill)

  • James R. Goldenring

    (Vanderbilt University School of Medicine
    Vanderbilt University School of Medicine
    Vanderbilt University School of Medicine
    Nashville VA Medical Center)

  • Eunyoung Choi

    (Vanderbilt University School of Medicine
    Vanderbilt University School of Medicine)

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.

Suggested Citation

  • Jimin Min & Paige N. Vega & Amy C. Engevik & Janice A. Williams & Qing Yang & Loraine M. Patterson & Alan J. Simmons & R. Jarrett Bliton & Joshua W. Betts & Ken S. Lau & Scott T. Magness & James R. Go, 2019. "Heterogeneity and dynamics of active Kras-induced dysplastic lineages from mouse corpus stomach," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13479-6
    DOI: 10.1038/s41467-019-13479-6
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