Single-cell lineage analysis reveals genetic and epigenetic interplay in glioblastoma drug resistance
| Autor: | Volker Hovestadt, Christine E. Eyler, Peter van Galen, Hironori Matsunaga, Samantha J. Vantine, Bradley E. Bernstein |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Tumor heterogeneity
Receptor Platelet-Derived Growth Factor alpha lcsh:QH426-470 Dasatinib Antineoplastic Agents Computational biology Lineage tracing Receptor tyrosine kinase Epigenesis Genetic Transcriptome Clonal Evolution Insulin receptor substrate/IRS Genetic Humans Glioma stem cells Epigenetics Protein kinase B lcsh:QH301-705.5 Single-cell RNA-seq biology Genetic heterogeneity Sequence Analysis RNA Research Therapy resistance Epigenetic Phenotype Human genetics Insulin receptor lcsh:Genetics lcsh:Biology (General) Drug Resistance Neoplasm biology.protein Insulin Receptor Substrate Proteins Single-Cell Analysis Glioblastoma |
| Zdroj: | Genome Biology, Vol 21, Iss 1, Pp 1-21 (2020) Genome Biology |
| Popis: | Background Tumors can evolve and adapt to therapeutic pressure by acquiring genetic and epigenetic alterations that may be transient or stable. A precise understanding of how such events contribute to intratumoral heterogeneity, dynamic subpopulations, and overall tumor fitness will require experimental approaches to prospectively label, track, and characterize resistant or otherwise adaptive populations at the single-cell level. In glioblastoma, poor efficacy of receptor tyrosine kinase (RTK) therapies has been alternatively ascribed to genetic heterogeneity or to epigenetic transitions that circumvent signaling blockade. Results We combine cell lineage barcoding and single-cell transcriptomics to trace the emergence of drug resistance in stem-like glioblastoma cells treated with RTK inhibitors. Whereas a broad variety of barcoded lineages adopt a Notch-dependent persister phenotype that sustains them through early drug exposure, rare subclones acquire genetic changes that enable their rapid outgrowth over time. Single-cell analyses reveal that these genetic subclones gain copy number amplifications of the insulin receptor substrate-1 and substrate-2 (IRS1 or IRS2) loci, which activate insulin and AKT signaling programs. Persister-like cells and genomic amplifications of IRS2 and other loci are evident in primary glioblastomas and may underlie the inefficacy of targeted therapies in this disease. Conclusions A method for combined lineage tracing and scRNA-seq reveals the interplay between complementary genetic and epigenetic mechanisms of resistance in a heterogeneous glioblastoma tumor model. |
| Databáze: | OpenAIRE |
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