Year: 2021
Type: preprint
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.
Source: Genes & Development
Language: English
Topic: Lung Cancer Research Studies
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: Genomic and Functional Identification of Chemotherapy Resistance Mechanisms in Small Cell Lung Cancer, G419867110, G4427614689, Phenotype Transitions in Small Cell Lung Cancer, G7443545732, G7941272330, Identifying Therapeutic Vulnerabilities of c-MYC-driven Small Cell Lung Cancer, G8314062768, Cancer Center Support Grant, Coordinating center for the NCI small cell lung cancer research consortium, Developing ASCL1 and NeuroD1 lineage oncogene targeted therapy for small cell lung cancer
OpenAlex ID: W3162275996