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Series GSE243562 Query DataSets for GSE243562
Status Public on Feb 06, 2024
Title ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts [scRNA-seq]
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKIs). However, most of these responses are partial with drug tolerant residual disease remaining even at the time of maximal response. This residual disease ultimately leads to relapses which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the 3rd generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally, but not mutationally, distinct from bulk pre-treatment tumor. Using single cell transcriptional profiling we found evidence of cells matching the profiles of drug-tolerant cells present in the pre-treatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, we found that ASCL1 confers drug tolerance by initiating an epithelial-to-mesenchymal gene expression program in permissive cellular contexts. Our study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment and explains why specific phenotypes are only observed in certain tumors.
 
Overall design To investigate the cellular heterogeneity in the PDXs and its relationship with drug tolerance, untreated and residual tumor tissues were analyzed with scRNA-seq.
 
Contributor(s) Hu B, Zhao D, Chan L, Melnick MA, Wurtz A, Yan Q, Politi K
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Submission date Sep 19, 2023
Last update date Feb 07, 2024
Contact name Bomiao Hu
E-mail(s) bomiao.hu@yale.edu
Organization name Yale University
Street address 310 Cedar Street
City New Haven
State/province CT
ZIP/Postal code 06519
Country USA
 
Platforms (1)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
Samples (4)
GSM7790998 YU-003 PDX, untreated
GSM7790999 YU-003 PDX, residual
GSM7791000 YU-006 PDX, untreated
This SubSeries is part of SuperSeries:
GSE243569 ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts
Relations
BioProject PRJNA1018935

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Supplementary file Size Download File type/resource
GSE243562_RAW.tar 197.9 Mb (http)(custom) TAR (of MTX, TSV)
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Raw data are available in SRA

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