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ASCL1 represses a SOX9+ neural crest stem-like state in small cell lung cancer.

Publication ,  Journal Article
Olsen, RR; Ireland, AS; Kastner, DW; Groves, SM; Spainhower, KB; Pozo, K; Kelenis, DP; Whitney, CP; Guthrie, MR; Wait, SJ; Soltero, D ...
Published in: Genes Dev
June 2021

ASCL1 is a neuroendocrine lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, ∼25% of human SCLC are ASCL1-low and associated with low neuroendocrine fate and high MYC expression. Using genetically engineered mouse models (GEMMs), we show that alterations in Rb1/Trp53/Myc in the mouse lung induce an ASCL1+ state of SCLC in multiple cells of origin. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation and progression to the NEUROD1+ subtype of SCLC. Surprisingly, ASCL1 loss promotes a SOX9+ mesenchymal/neural crest stem-like state and the emergence of osteosarcoma and chondroid tumors, whose propensity is impacted by cell of origin. ASCL1 is critical for expression of key lineage-related transcription factors NKX2-1, FOXA2, and INSM1 and represses genes involved in the Hippo/Wnt/Notch developmental pathways in vivo. Importantly, ASCL1 represses a SOX9/RUNX1/RUNX2 program in vivo and SOX9 expression in human SCLC cells, suggesting a conserved function for ASCL1. Together, in a MYC-driven SCLC model, ASCL1 promotes neuroendocrine fate and represses the emergence of a SOX9+ nonendodermal stem-like fate that resembles neural crest.

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Published In

Genes Dev

DOI

EISSN

1549-5477

Publication Date

June 2021

Volume

35

Issue

11-12

Start / End Page

847 / 869

Location

United States

Related Subject Headings

  • Stem Cells
  • Small Cell Lung Carcinoma
  • SOX9 Transcription Factor
  • Neural Crest
  • Mice
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Disease Models, Animal
  • Developmental Biology
  • Basic Helix-Loop-Helix Transcription Factors
 

Citation

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Olsen, R. R., Ireland, A. S., Kastner, D. W., Groves, S. M., Spainhower, K. B., Pozo, K., … Oliver, T. G. (2021). ASCL1 represses a SOX9+ neural crest stem-like state in small cell lung cancer. Genes Dev, 35(11–12), 847–869. https://doi.org/10.1101/gad.348295.121
Olsen, Rachelle R., Abbie S. Ireland, David W. Kastner, Sarah M. Groves, Kyle B. Spainhower, Karine Pozo, Demetra P. Kelenis, et al. “ASCL1 represses a SOX9+ neural crest stem-like state in small cell lung cancer.Genes Dev 35, no. 11–12 (June 2021): 847–69. https://doi.org/10.1101/gad.348295.121.
Olsen RR, Ireland AS, Kastner DW, Groves SM, Spainhower KB, Pozo K, et al. ASCL1 represses a SOX9+ neural crest stem-like state in small cell lung cancer. Genes Dev. 2021 Jun;35(11–12):847–69.
Olsen, Rachelle R., et al. “ASCL1 represses a SOX9+ neural crest stem-like state in small cell lung cancer.Genes Dev, vol. 35, no. 11–12, June 2021, pp. 847–69. Pubmed, doi:10.1101/gad.348295.121.
Olsen RR, Ireland AS, Kastner DW, Groves SM, Spainhower KB, Pozo K, Kelenis DP, Whitney CP, Guthrie MR, Wait SJ, Soltero D, Witt BL, Quaranta V, Johnson JE, Oliver TG. ASCL1 represses a SOX9+ neural crest stem-like state in small cell lung cancer. Genes Dev. 2021 Jun;35(11–12):847–869.

Published In

Genes Dev

DOI

EISSN

1549-5477

Publication Date

June 2021

Volume

35

Issue

11-12

Start / End Page

847 / 869

Location

United States

Related Subject Headings

  • Stem Cells
  • Small Cell Lung Carcinoma
  • SOX9 Transcription Factor
  • Neural Crest
  • Mice
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Disease Models, Animal
  • Developmental Biology
  • Basic Helix-Loop-Helix Transcription Factors