@article{ca89d93ddc78424d924fd07affedae58,
title = "MYC Drives Temporal Evolution of Small Cell Lung Cancer Subtypes by Reprogramming Neuroendocrine Fate",
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.",
keywords = "ASCL1, MYC, NEUROD1, NOTCH, SCLC, YAP1, mouse models, neuroendocrine, plasticity, tumor evolution",
author = "Ireland, {Abbie S.} and Micinski, {Alexi M.} and Kastner, {David W.} and Bingqian Guo and Wait, {Sarah J.} and Spainhower, {Kyle B.} and Conley, {Christopher C.} and Chen, {Opal S.} and Guthrie, {Matthew R.} and Danny Soltero and Yi Qiao and Xiaomeng Huang and Szabolcs Tarapcs{\'a}k and Siddhartha Devarakonda and Chalishazar, {Milind D.} and Jason Gertz and Moser, {Justin C.} and Gabor Marth and Sonam Puri and Witt, {Benjamin L.} and Spike, {Benjamin T.} and Oliver, {Trudy G.}",
note = "Funding Information: We thank members of the Oliver Lab for technical assistance and mouse colony management, R. Olsen, R. Dahlgren, and L. Houston for administrative support, A. Andersen for editorial guidance, and B. Dalley, K. Rondem, and C. Stubben for bioinformatics support. We are grateful to our late colleague Dr. Adi Gazdar for insightful discussions and inspiration for this work. We acknowledge support from the National Cancer Institute (NCI) of the NIH under award P30CA042014 to Huntsman Cancer Institute for the use of core facilities and shared resources, including Biorepository and Molecular Pathology, High-Throughput Genomics and Bioinformatic Analysis, and Flow Cytometry Shared Resources; we acknowledge support and resources from the Center for High Performance Computing at the University of Utah . T.G.O. was supported in part by NIH NCI ( U01-CA231844 , U24-CA213274 and R21-CA216504-01A1 ). Funding Information: We thank members of the Oliver Lab for technical assistance and mouse colony management, R. Olsen, R. Dahlgren, and L. Houston for administrative support, A. Andersen for editorial guidance, and B. Dalley, K. Rondem, and C. Stubben for bioinformatics support. We are grateful to our late colleague Dr. Adi Gazdar for insightful discussions and inspiration for this work. We acknowledge support from the National Cancer Institute (NCI) of the NIH under award P30CA042014 to Huntsman Cancer Institute for the use of core facilities and shared resources, including Biorepository and Molecular Pathology, High-Throughput Genomics and Bioinformatic Analysis, and Flow Cytometry Shared Resources; we acknowledge support and resources from the Center for High Performance Computing at the University of Utah. T.G.O. was supported in part by NIH NCI (U01-CA231844, U24-CA213274 and R21-CA216504-01A1). Study Design, A.S.I. and T.G.O.; Data Analysis and Acquisition, A.S.I. A.M.M. D.W.K. O.S.C. S.J.W. K.B.S. M.R.G. D.S. B.G. M.D.C. and J.G.; Bioinformatic Analyses, A.S.I. C.C.C. Y.Q. X.H. S.T. S.D. G.M. B.T.S. and J.G.; Pathology, B.L.W.; Clinical Annotation, S.P. and J.C.M.; Study Supervision and Funding, T.G.O.; Manuscript Preparation, A.S.I. B.T.S. and T.G.O. T.G.O. has pending patent applications related to subtype stratification of SCLC: US16/335368, JP2019522392, and EP2017865057. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = jul,
day = "13",
doi = "10.1016/j.ccell.2020.05.001",
language = "English",
volume = "38",
pages = "60--78.e12",
journal = "Cancer Cell",
issn = "1535-6108",
number = "1",
}