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

Rachelle R. Olsen, Abbie S. Ireland, David W. Kastner, Sarah M. Groves, Kyle B. Spainhower, Karine Pozo, Demetra P. Kelenis, Christopher P. Whitney, Matthew R. Guthrie, Sarah J. Wait, Danny Soltero, Benjamin L. Witt, Vito Quaranta, Jane E. Johnson, Trudy G. Oliver

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-23
Number of pages23
JournalGenes and Development
Volume38
Issue number11-12
DOIs
StatePublished - Jun 1 2021

Keywords

  • ASCL1
  • Cell of origin
  • Lung cancer
  • Mouse models
  • Neuroendocrine
  • Plasticity
  • SCLC
  • Small cell lung cancer]

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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