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Beyondcell: targeting cancer therapeutic heterogeneity in single-cell RNA-seq

View ORCID ProfileCoral Fustero-Torre, María José Jiménez-Santos, Santiago García-Martín, Carlos Carretero-Puche, Luis García-Jimeno, Tomás Di Domenico, Gonzalo Gómez-López, Fátima Al-Shahrour
doi: https://doi.org/10.1101/2021.04.08.438954
Coral Fustero-Torre
1Spanish National Cancer Research Centre (CNIO), Unidad de Investigación en tumores Digestivos, Instituto de Investigación I+12, Hospital 12 de Octubre, Madrid, Spain
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  • ORCID record for Coral Fustero-Torre
María José Jiménez-Santos
1Spanish National Cancer Research Centre (CNIO), Unidad de Investigación en tumores Digestivos, Instituto de Investigación I+12, Hospital 12 de Octubre, Madrid, Spain
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Santiago García-Martín
1Spanish National Cancer Research Centre (CNIO), Unidad de Investigación en tumores Digestivos, Instituto de Investigación I+12, Hospital 12 de Octubre, Madrid, Spain
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Carlos Carretero-Puche
2Laboratorio de Oncología Clínico-Traslacional, Unidad de Investigación en tumores Digestivos, Instituto de Investigación I+12, Hospital 12 de Octubre, Madrid, Spain
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Luis García-Jimeno
1Spanish National Cancer Research Centre (CNIO), Unidad de Investigación en tumores Digestivos, Instituto de Investigación I+12, Hospital 12 de Octubre, Madrid, Spain
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Tomás Di Domenico
1Spanish National Cancer Research Centre (CNIO), Unidad de Investigación en tumores Digestivos, Instituto de Investigación I+12, Hospital 12 de Octubre, Madrid, Spain
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Gonzalo Gómez-López
1Spanish National Cancer Research Centre (CNIO), Unidad de Investigación en tumores Digestivos, Instituto de Investigación I+12, Hospital 12 de Octubre, Madrid, Spain
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Fátima Al-Shahrour
1Spanish National Cancer Research Centre (CNIO), Unidad de Investigación en tumores Digestivos, Instituto de Investigación I+12, Hospital 12 de Octubre, Madrid, Spain
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  • For correspondence: falshahrour@cnio.es
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Abstract

We present Beyondcell (https://gitlab.com/bu_cnio/beyondcell/), a computational methodology for identifying tumour cell subpopulations with distinct drug responses in single-cell RNA-seq data and proposing cancer-specific treatments. Our method calculates an enrichment score in a collection of drug signatures, delineating therapeutic clusters (TCs) within cellular populations. Additionally, Beyondcell determines therapeutic differences among cell populations, and generates a prioritised ranking of the differential sensitivity drugs between chosen conditions to guide drug selection. We performed Beyondcell analysis in four single-cell datasets to validate our score and to demonstrate that TCs can be exploited to target malignant cells both in cancer cell lines and tumour patients.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://gitlab.com/bu_cnio/beyondcell/

  • List of abbreviations

    TCs
    Therapeutic clusters
    TH
    Tumour heterogeneity
    scRNA-seq
    Single-cell RNA sequencing
    CCLE
    Cancer Cell Line Encyclopedia
    GDSC
    Genomics of Drugs Sensitivity in Cancer
    CTRP
    Cancer Therapeutic Response Portal
    LINCS
    Library of Integrated Network-based Cellular Signatures
    PSC
    Drug perturbation signature collection
    SSC
    Drug sensitivity signature collection
    MSigDB
    Molecular Signatures Database
    EMT
    Epithelial-mesenchymal transition
    SP
    Switch Point
    BCS
    Beyondcell score
    DSS
    Drug Specificity Score
    KNN
    k-Nearest Neighbours
    UMAP
    Uniform Manifold Approximation and Projection
    PCA
    Principal Components Analysis
    HSP
    Heat Shock Proteins
    RHPs
    Recurrently heterogeneous programs
    EpiSen
    Epithelial senescence-associated
    ICIs
    Immune Checkpoint Inhibitors
    CDKi
    CDK-inhibitor
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    Posted April 09, 2021.
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    Beyondcell: targeting cancer therapeutic heterogeneity in single-cell RNA-seq
    Coral Fustero-Torre, María José Jiménez-Santos, Santiago García-Martín, Carlos Carretero-Puche, Luis García-Jimeno, Tomás Di Domenico, Gonzalo Gómez-López, Fátima Al-Shahrour
    bioRxiv 2021.04.08.438954; doi: https://doi.org/10.1101/2021.04.08.438954
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    Beyondcell: targeting cancer therapeutic heterogeneity in single-cell RNA-seq
    Coral Fustero-Torre, María José Jiménez-Santos, Santiago García-Martín, Carlos Carretero-Puche, Luis García-Jimeno, Tomás Di Domenico, Gonzalo Gómez-López, Fátima Al-Shahrour
    bioRxiv 2021.04.08.438954; doi: https://doi.org/10.1101/2021.04.08.438954

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