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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
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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.
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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.
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Contributor(s) |
Ireland AS, Olsen RR, Oliver TG |
Citation(s) |
34016693 |
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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
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Phone |
6174607487
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Organization name |
Duke University
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Department |
Pharmacology & Cancer Biology
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Lab |
theoliverlab
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Street address |
Duke University, Box 3813, LSRC Room C138B, 308 Research Drive
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City |
Durham |
State/province |
NC |
ZIP/Postal code |
27708 |
Country |
USA |
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Platforms (1) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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Samples (4)
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This SubSeries is part of SuperSeries: |
GSE155692 |
ASCL1 represses a latent osteogenic program in small cell lung cancer in multiple cells of origin |
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Relations |
BioProject |
PRJNA716967 |
SRA |
SRP311968 |