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

• Published in: Genes & development Vol. 35; no. 11-12; pp. 847 - 869
• Main Authors: Olsen, Rachelle R, Ireland, Abbie S, Kastner, David W, Groves, Sarah M, Spainhower, Kyle B, Pozo, Karine, Kelenis, Demetra P, Whitney, Christopher P, Guthrie, Matthew R, Wait, Sarah J, Soltero, Danny, Witt, Benjamin L, Quaranta, Vito, Johnson, Jane E, Oliver, Trudy G
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01-06-2021
• Subjects: Research Paper; lung cancer; mouse models; SCLC; neuroendocrine; plasticity; small cell lung cancer; ASCL1; cell of origin
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.348295.121

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
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.