ASCL1 represses a SOX9<sup>+</sup> neural crest stem-like state in small cell lung cancer
説明
<jats:p>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 <jats:italic>Rb1/Trp53/Myc</jats:italic> in the mouse lung induce an ASCL1<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup> subtype of SCLC. Surprisingly, ASCL1 loss promotes a SOX9<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup> nonendodermal stem-like fate that resembles neural crest.</jats:p>
収録刊行物
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- Genes & Development
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Genes & Development 35 (11-12), 847-869, 2021-05-20
Cold Spring Harbor Laboratory
