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Single-Cell Analysis Reveals Transcriptomic Features of Drug-Tolerant Persisters and Stromal Adaptation in a Patient-Derived EGFR-Mutated Lung Adenocarcinoma Xenograft Model.
- Source :
-
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer [J Thorac Oncol] 2023 Apr; Vol. 18 (4), pp. 499-515. Date of Electronic Publication: 2022 Dec 16. - Publication Year :
- 2023
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Abstract
- Introduction: Targeted therapies require life-long treatment, as drug discontinuation invariably leads to tumor recurrence. Recurrence is mainly driven by minor subpopulations of drug-tolerant persister (DTP) cells that survive the cytotoxic drug effect. In lung cancer, DTP studies have mainly been conducted with cell line models.<br />Methods: We conducted an in vivo DTP study using a lung adenocarcinoma patient-derived xenograft tumor driven by an EGFR mutation. Daily treatment of tumor-bearing mice for 5 to 6 weeks with the EGFR inhibitor erlotinib markedly shrunk tumors and generated DTPs, which were analyzed by whole exome, bulk population transcriptome, and single-cell RNA sequencing.<br />Results: The DTP tumors maintained the genomic clonal architecture of untreated baseline (BL) tumors but had reduced proliferation. Single-cell RNA sequencing identified a rare (approximately 4%) subpopulation of BL cells (DTP-like) with transcriptomic similarity to DTP cells and intermediate activity of pathways that are up-regulated in DTPs. Furthermore, the predominant transforming growth factor-β activated cancer-associated fibroblast (CAF) population in BL tumors was replaced by a CAF population enriched for IL6 production. In vitro experiments indicate that these populations interconvert depending on the levels of transforming growth factor-β versus NF-κB signaling, which is modulated by tyrosine kinase inhibitor presence. The DTPs had signs of increased NF-κB and STAT3 signaling, which may promote their survival.<br />Conclusions: The DTPs may arise from a specific preexisting subpopulation of cancer cells with partial activation of specific drug resistance pathways. Tyrosine kinase inhibitor treatment induces DTPs revealing greater activation of these pathways while converting the major preexisting CAF population into a new state that may further promote DTP survival.<br /> (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Animals
Mice
Transcriptome
NF-kappa B genetics
NF-kappa B metabolism
NF-kappa B pharmacology
Heterografts
ErbB Receptors metabolism
Drug Resistance, Neoplasm genetics
Cell Line, Tumor
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors therapeutic use
Single-Cell Analysis
Transforming Growth Factors genetics
Transforming Growth Factors pharmacology
Transforming Growth Factors therapeutic use
Xenograft Model Antitumor Assays
Mutation
Lung Neoplasms drug therapy
Lung Neoplasms genetics
Lung Neoplasms pathology
Adenocarcinoma of Lung drug therapy
Adenocarcinoma of Lung genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1556-1380
- Volume :
- 18
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 36535627
- Full Text :
- https://doi.org/10.1016/j.jtho.2022.12.003