MYC Drives Temporal Evolution of Small Cell Lung Cancer Subtypes by Reprogramming Neuroendocrine Fate

被引：333

作者：

Ireland, Abbie S. ^{[1
]}

Micinski, Alexi M. ^{[1
]}

Kastner, David W. ^{[1
]}

Guo, Bingqian ^{[1
]}

Wait, Sarah J. ^{[1
]}

Spainhower, Kyle B. ^{[1
]}

Conley, Christopher C. ^{[2
]}

Chen, Opal S. ^{[3
]}

Guthrie, Matthew R. ^{[1
]}

Soltero, Danny ^{[1
]}

Qiao, Yi ^{[4
]}

Huang, Xiaomeng ^{[4
]}

Tarapcsak, Szabolcs ^{[4
]}

Devarakonda, Siddhartha ^{[5
]}

Chalishazar, Milind D. ^{[1
]}

Gertz, Jason ^{[1
]}

Moser, Justin C. ^{[6
]}

Marth, Gabor ^{[4
]}

Puri, Sonam ^{[7
]}

Witt, Benjamin L. ^{[8
,9
]}

Spike, Benjamin T. ^{[1
]}

Oliver, Trudy G. ^{[1
]}

机构：

[1] Univ Utah, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA

[2] Univ Utah, Huntsman Canc Inst, Huntsman Canc Inst Bioinformat Anal Shared Resour, Salt Lake City, UT 84112 USA

[3] Univ Utah, Huntsman Canc Inst, Huntsman Canc Inst High Throughput Genom Shared R, Salt Lake City, UT 84112 USA

[4] Univ Utah, Eccles Inst Human Genet, Utah Ctr Genet Discovery, Salt Lake City, UT 84112 USA

[5] Washington Univ, Sch Med, Dept Med, Div Med Oncol, St Louis, MO 63110 USA

[6] HonorHlth Res Inst, Scottsdale, AZ 85254 USA

[7] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA

[8] Univ Utah, Dept Pathol, Salt Lake City, UT 84112 USA

[9] Univ Utah, ARUP Labs, Salt Lake City, UT 84108 USA

来源：

CANCER CELL | 2020年 / 38卷 / 01期

关键词：

EPITHELIAL-CELLS; HETEROGENEITY; GENOME; ORIGIN; EXPRESSION; MODELS; LINES; DIFFERENTIATION; INACTIVATION; PROGRESSION;

D O I：

10.1016/j.ccell.2020.05.001

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：60 / +

页数：31

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