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

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. WittBenjamin T. Spike, Trudy G. Oliver

Research output: Contribution to journal › Article › peer-review

253 Scopus citations

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.

Original language	English
Pages (from-to)	60-78.e12
Journal	Cancer Cell
Volume	38
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2020.05.001
State	Published - Jul 13 2020

Keywords

ASCL1
MYC
NEUROD1
NOTCH
SCLC
YAP1
mouse models
neuroendocrine
plasticity
tumor evolution

Access to Document

10.1016/j.ccell.2020.05.001

Cite this

Ireland, A. S., Micinski, A. M., Kastner, D. W., Guo, B., Wait, S. J., Spainhower, K. B., Conley, C. C., Chen, O. S., Guthrie, M. R., Soltero, D., Qiao, Y., Huang, X., Tarapcsák, S., Devarakonda, S., Chalishazar, M. D., Gertz, J., Moser, J. C., Marth, G., Puri, S., ... Oliver, T. G. (2020). MYC Drives Temporal Evolution of Small Cell Lung Cancer Subtypes by Reprogramming Neuroendocrine Fate. Cancer Cell, 38(1), 60-78.e12. https://doi.org/10.1016/j.ccell.2020.05.001

@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 = "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",

}

Ireland, AS, Micinski, AM, Kastner, DW, Guo, B, Wait, SJ, Spainhower, KB, Conley, CC, Chen, OS, Guthrie, MR, Soltero, D, Qiao, Y, Huang, X, Tarapcsák, S, Devarakonda, S, Chalishazar, MD, Gertz, J, Moser, JC, Marth, G, Puri, S, Witt, BL, Spike, BT & Oliver, TG 2020, 'MYC Drives Temporal Evolution of Small Cell Lung Cancer Subtypes by Reprogramming Neuroendocrine Fate', Cancer Cell, vol. 38, no. 1, pp. 60-78.e12. https://doi.org/10.1016/j.ccell.2020.05.001

TY - JOUR

T1 - MYC Drives Temporal Evolution of Small Cell Lung Cancer Subtypes by Reprogramming Neuroendocrine Fate

AU - Ireland, Abbie S.

AU - Micinski, Alexi M.

AU - Kastner, David W.

AU - Guo, Bingqian

AU - Wait, Sarah J.

AU - Spainhower, Kyle B.

AU - Conley, Christopher C.

AU - Chen, Opal S.

AU - Guthrie, Matthew R.

AU - Soltero, Danny

AU - Qiao, Yi

AU - Huang, Xiaomeng

AU - Tarapcsák, Szabolcs

AU - Devarakonda, Siddhartha

AU - Chalishazar, Milind D.

AU - Gertz, Jason

AU - Moser, Justin C.

AU - Marth, Gabor

AU - Puri, Sonam

AU - Witt, Benjamin L.

AU - Spike, Benjamin T.

AU - Oliver, Trudy G.

PY - 2020/7/13

Y1 - 2020/7/13

N2 - 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.

AB - 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.

KW - ASCL1

KW - MYC

KW - NEUROD1

KW - NOTCH

KW - SCLC

KW - YAP1

KW - mouse models

KW - neuroendocrine

KW - plasticity

KW - tumor evolution

UR - http://www.scopus.com/inward/record.url?scp=85085593809&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2020.05.001

DO - 10.1016/j.ccell.2020.05.001

M3 - Article

C2 - 32473656

AN - SCOPUS:85085593809

SN - 1535-6108

VL - 38

SP - 60-78.e12

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this