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

Abbie S Ireland; Alexi M Micinski; David W Kastner; Bingqian Guo; Sarah J Wait; Kyle B Spainhower; Christopher C Conley; Opal S Chen; Matthew R Guthrie; Danny Soltero; Yi Qiao; Xiaomeng Huang; Szabolcs Tarapcsák; Siddhartha Devarakonda; Milind D Chalishazar; Jason Gertz; Justin C Moser; Gabor Marth; Sonam Puri; Benjamin L Witt; Benjamin T Spike; Trudy G Oliver

doi:10.1016/j.ccell.2020.05.001

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

Cancer Cell. 2020 Jul 13;38(1):60-78.e12. doi: 10.1016/j.ccell.2020.05.001. Epub 2020 May 30.

Authors

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

Affiliations

¹ Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
² Huntsman Cancer Institute Bioinformatic Analysis Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
³ Huntsman Cancer Institute High-Throughput Genomics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
⁴ Utah Center for Genetic Discovery, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
⁵ Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁶ HonorHealth Research Institute, Scottsdale, AZ 85254, USA.
⁷ Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA.
⁸ Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA; ARUP Laboratories at University of Utah, Salt Lake City, UT 84108, USA.
⁹ Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: trudy.oliver@hci.utah.edu.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Line, Tumor
Disease Models, Animal
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic*
Genetic Heterogeneity
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Mice, Knockout
Neuroendocrine Tumors / genetics*
Neuroendocrine Tumors / metabolism
Proto-Oncogene Proteins c-myc / genetics*
Proto-Oncogene Proteins c-myc / metabolism
Receptors, Notch / genetics
Receptors, Notch / metabolism
Signal Transduction / genetics
Single-Cell Analysis
Small Cell Lung Carcinoma / genetics*
Small Cell Lung Carcinoma / metabolism

Substances

MYC protein, human
Proto-Oncogene Proteins c-myc
Receptors, Notch

Abstract

Publication types

MeSH terms

Substances

Grants and funding