| Literature DB >> 32473656 |
Abbie S Ireland1, Alexi M Micinski1, David W Kastner1, Bingqian Guo1, Sarah J Wait1, Kyle B Spainhower1, Christopher C Conley2, Opal S Chen3, Matthew R Guthrie1, Danny Soltero1, Yi Qiao4, Xiaomeng Huang4, Szabolcs Tarapcsák4, Siddhartha Devarakonda5, Milind D Chalishazar1, Jason Gertz1, Justin C Moser6, Gabor Marth4, Sonam Puri7, Benjamin L Witt8, Benjamin T Spike1, Trudy G Oliver9.
Abstract
Small cell lung cancer (SCLC) is a neuroendocrine tumor treated clinically as a single disease with poor outcomes. Distinct SCLC molecular subtypes have been defined based on expression of ASCL1, NEUROD1, POU2F3, or YAP1. Here, we use mouse and human models with a time-series single-cell transcriptome analysis to reveal that MYC drives dynamic evolution of SCLC subtypes. In neuroendocrine cells, MYC activates Notch to dedifferentiate tumor cells, promoting a temporal shift in SCLC from ASCL1+ to NEUROD1+ to YAP1+ states. MYC alternatively promotes POU2F3+ tumors from a distinct cell type. Human SCLC exhibits intratumoral subtype heterogeneity, suggesting that this dynamic evolution occurs in patient tumors. These findings suggest that genetics, cell of origin, and tumor cell plasticity determine SCLC subtype.Entities:
Keywords: ASCL1; MYC; NEUROD1; NOTCH; SCLC; YAP1; mouse models; neuroendocrine; plasticity; tumor evolution
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Year: 2020 PMID： 32473656 PMCID： PMC7393942 DOI： 10.1016/j.ccell.2020.05.001
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743