Evidence map›Paper›PMID 32669109›Full record

ArticleGenome biology2020

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

Christine E Eyler, Hironori Matsunaga, Volker Hovestadt, Samantha J Vantine, Peter van Galen, Bradley E Bernstein

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Genome biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers.

0numbers the graph read from it
0cells of the map it votes in
83citing papers in PubMed
8.1field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

83 citing papers in PubMed, 104 citations in OpenAlex.

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  14. Cell lineage tracing: Methods, applications, and challenges.Quantitative biology (Beijing, China) · 2025
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23 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

6 authors at 4 institutions in 1 country.

Christine E EylerDepartment of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Hironori MatsunagaBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Volker HovestadtBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Samantha J VantineBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Peter van GalenBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Bradley E BernsteinBroad Institute of Harvard and MIT, Cambridge, MA, USA. bernstein.bradley@mgh.harvard.edu.
Broad Institute · USMassachusetts General Hospital · USCenter for Cancer Research · USHarvard University · US

Funding

Institutional Career Development CoreKL2TR002542 · NCATS · HARVARD MEDICAL SCHOOL · PI BREDELLA, MIRIAM ANTOINETTE, RUTKOVE, SEWARD B. · 2018 to 2022
$8.7M
Epigenetic plasticity in tumor initiation and evolutionDP1CA216873 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI BERNSTEIN, BRADLEY EVAN · 2016 to 2020
$5.9M
NCATS NIH HHS KL2 TR002542NCI NIH HHS DP1 CA216873
6 · The paper itself

Abstract

backgroundTumors 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.

resultsWe 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.

conclusionsA 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.

Indexed as

Antineoplastic AgentsClonal EvolutionDasatinibDrug Resistance, NeoplasmEpigenesis, GeneticGlioblastomaHumansInsulin Receptor Substrate ProteinsReceptor, Platelet-Derived Growth Factor alphaSequence Analysis, RNASingle-Cell AnalysisAntineoplastic AgentsDasatinibInsulin Receptor Substrate ProteinsIRS1 protein, humanIRS2 protein, humanReceptor, Platelet-Derived Growth Factor alphaEpigeneticGeneticGlioma stem cellsInsulin receptor substrate/IRSLineage tracingSingle-cell RNA-seqTherapy resistanceTumor heterogeneity

Identifiers

PMID32669109
PMCPMC7364565
OpenAlexW3042608540

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.