期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-13479-6
关键词
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资金
- DOD [CA160399, CA160479]
- AACR [17-20-41-CHOI]
- ACS [IRG-15-169-56]
- NIH [P30 DK058404, R01 DK071590, R01 DK101332, R01 DK103831]
- Department of Veterans Affairs Merit Review Award [IBX000930]
- China Scholarship Council [201706225033]
- VA Shared Instrumentation grant [1IS1BX003097]
- UNC Chapel Hill Center for GI Biology and Disease Imaging Core [P30 DK34987]
- [DK111101]
- [T32 HD007502]
- [U01 CA215798]
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 Mistl-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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