| First Author | Olsen RR | Year | 2021 |
| Journal | Genes Dev | Volume | 35 |
| Issue | 11-12 | Pages | 847-869 |
| PubMed ID | 34016693 | Mgi Jnum | J:346076 |
| Mgi Id | MGI:7612611 | Doi | 10.1101/gad.348295.121 |
| Citation | Olsen RR, et al. (2021) ASCL1 represses a SOX9(+) neural crest stem-like state in small cell lung cancer. Genes Dev 35(11-12):847-869 |
| abstractText | ASCL1 is a neuroendocrine lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, approximately 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. |
