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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • June 2021

Published In

Volume / Issue

  • 35 / 11-12

Start / End Page

  • 847 - 869

PubMed ID

  • 34016693

Pubmed Central ID

  • PMC8168563

Electronic International Standard Serial Number (EISSN)

  • 1549-5477

Digital Object Identifier (DOI)

  • 10.1101/gad.348295.121


  • eng

Conference Location

  • United States