@article{23b7896cb0584ea5aff9bb351b83658f,
title = "ASCL1 represses a SOX9+ neural crest stem-like state in small cell lung cancer",
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.",
keywords = "ASCL1, Cell of origin, Lung cancer, Mouse models, Neuroendocrine, Plasticity, SCLC, Small cell lung cancer]",
author = "Olsen, {Rachelle R.} and Ireland, {Abbie S.} and Kastner, {David W.} and Groves, {Sarah M.} and Spainhower, {Kyle B.} and Karine Pozo and Kelenis, {Demetra P.} and Whitney, {Christopher P.} and Guthrie, {Matthew R.} and Wait, {Sarah J.} and Danny Soltero and Witt, {Benjamin L.} and Vito Quaranta and Johnson, {Jane E.} and Oliver, {Trudy G.}",
note = "Funding Information: We appreciate Dr. Anton Berns for permission to use AdCre viruses deposited at University of Iowa. We are grateful to the late Dr. Adi Gazdar, who provided insightful pathological observations for this study. We thank R. Dahlgren and L. Houston for administrative assistance and members of the Oliver lab, especially D. Hansen, P. Ballieu, and A. Micinski for mouse colony management. We acknowledge support from the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under award P30CA042014 to Huntsman Cancer Institute for the use of core facilities and shared resources, including Biorepository and Molecular Pathology, High-Throughput Genomics and Bio-informatic Analysis, and DNA Sequencing. This work was supported by the NIH/NCI (R21-CA216504-01A1, U01-CA231844, U01-CA213338, and U24-CA213274). Funding Information: We appreciate Dr. Anton Berns for permission to use AdCre viruses deposited at University of Iowa. We are grateful to the late Dr. Adi Gazdar, who provided insightful pathological observations for this study. We thank R. Dahlgren and L. Houston for administrative assistance and members of the Oliver lab, especially D. Hansen, P. Ballieu, and A. Micinski for mouse colony management. We acknowledge support from the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under award P30CA042014 to Huntsman Cancer Institute for the use of core facilities and shared resources, including Biorepository and Molecular Pathology, High-Throughput Genomics and Bioinformatic Analysis, and DNA Sequencing. This work was supported by the NIH/NCI (R21-CA216504-01A1, U01-CA231844, U01-CA213338, and U24-CA213274). Publisher Copyright: {\textcopyright} 2021 Olsen et al.",
year = "2021",
month = jun,
day = "1",
doi = "10.1101/gad.348295.121",
language = "English (US)",
volume = "38",
pages = "1--23",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "11-12",
}