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Series GSE169529 Query DataSets for GSE169529
Status Public on May 22, 2021
Title ASCL1 represses a SOX9+ neural-crest-stem-like state in small cell lung cancer
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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 bone and more rarely, cartilaginous tumors. ASCL1 is critical for expression of key lineage-related transcription factors NKX2-1, FOXA2, and INSM1, and represses regulators of Hippo, Wnt and Notch developmental pathways in vivo. ASCL1 also represses SOX9 expression in human SCLC cells, suggesting a conserved function for ASCL1. Here, we utilize single-cell RNA sequencing to capture transcriptomic signatures of RPM (Rb1/Trp53/Myc), RPR2 (Rb1/Trp53/Rbl2), and RPMA (Rb1/Trp53/Myc/Ascl1) GEMM tumors to support our conclusion that in MYC-driven SCLC, ASCL1 promotes neuroendocrine fate and represses the emergence of SOX9+ non-endodermal stem-like or mesenchymal fates. These data were integrated with 4 additional invasive RPM tumors from NCBI GEO: GSE149180.
 
Overall design Single-cell RNA-sequencing using 10X platform on 1 RPMA tumor initiated with CMV-Cre (general promoter), 1 RPMA tumor initiated with CGRP-Cre (neuroendocrine cell-specific promoter), 1 early RPM tumor initiated with CGRP-Cre, and 1 RPR2 tumor initiated with CGRP-Cre. Tumors were digested with an enzymatic cocktail into single cell suspension and subject to 10X Chromium library preparation and Illumina sequencing targeting ~200M reads per sample.
 
Contributor(s) Ireland AS, Olsen RR, Oliver TG
Citation(s) 34016693
Submission date Mar 24, 2021
Last update date Sep 12, 2023
Contact name Trudy Oliver
E-mail(s) tgo@duke.edu, trudy.oliver@duke.edu
Phone 6174607487
Organization name Duke University
Department Pharmacology & Cancer Biology
Lab theoliverlab
Street address Duke University, Box 3813, LSRC Room C138B, 308 Research Drive
City Durham
State/province NC
ZIP/Postal code 27708
Country USA
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (4)
GSM5208891 18602X1 RPMA CMV
GSM5208892 18538X2 RPMA CGRP
GSM5208893 18571X2 RPM CGRP
This SubSeries is part of SuperSeries:
GSE155692 ASCL1 represses a latent osteogenic program in small cell lung cancer in multiple cells of origin
Relations
BioProject PRJNA716967
SRA SRP311968

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Supplementary file Size Download File type/resource
GSE169529_RAW.tar 133.6 Mb (http)(custom) TAR (of MTX, TSV)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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