Single-cell lineage analysis reveals genetic and epigenetic interplay in glioblastoma drug resistance.

Genome Biology
Christine E EylerBradley E Bernstein

Abstract

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. 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...Continue Reading

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Citations

Oct 21, 2020·Cells·Elena ParmigianiClaudio Giachino
Jan 15, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Jean AcostaPeter van Galen
Dec 29, 2020·Neuro-oncology·Jeff C CarlsonBenjamin Deneen
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Feb 12, 2021·European Journal of Immunology·Emily StephensonMuzlifah Haniffa
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May 18, 2021·Current Opinion in Systems Biology·Lingfei WangLuca Pinello
Sep 30, 2021·Nature Reviews. Cancer·Brian M AndersenFrancisco J Quintana
Oct 3, 2021·Genome Research·Dalia BarkleyItai Yanai

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Methods Mentioned

BETA
scRNA-seq
RNA-seq
single-cell sequencing
restriction digest
flow cytometry
PCRs
PCR
Illumina sequencing
Seq-Well

Software Mentioned

STAR
ImageJ
Liger
xenabrowser
bcl2fastq
igvtools count
R language
Base32
PharmacoGx package
Fastq

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