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A loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways

Author

Listed:
  • Martin F. M. Rooij

    (Amsterdam UMC location University of Amsterdam
    Lymphoma and Myeloma Center Amsterdam (LYMMCARE)
    Cancer Biology and Immunology - Target & Therapy Discovery)

  • Yvonne J. Thus

    (Amsterdam UMC location University of Amsterdam
    Lymphoma and Myeloma Center Amsterdam (LYMMCARE)
    Cancer Biology and Immunology - Target & Therapy Discovery)

  • Nathalie Swier

    (Amsterdam UMC location University of Amsterdam
    Lymphoma and Myeloma Center Amsterdam (LYMMCARE)
    Cancer Biology and Immunology - Target & Therapy Discovery)

  • Roderick L. Beijersbergen

    (The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Steven T. Pals

    (Amsterdam UMC location University of Amsterdam
    Lymphoma and Myeloma Center Amsterdam (LYMMCARE)
    Cancer Biology and Immunology - Target & Therapy Discovery)

  • Marcel Spaargaren

    (Amsterdam UMC location University of Amsterdam
    Lymphoma and Myeloma Center Amsterdam (LYMMCARE)
    Cancer Biology and Immunology - Target & Therapy Discovery)

Abstract

The clinical introduction of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which targets B-cell antigen-receptor (BCR)-controlled integrin-mediated retention of malignant B cells in their growth-supportive lymphoid organ microenvironment, provided a major breakthrough in lymphoma and leukemia treatment. Unfortunately, a significant subset of patients is intrinsically resistant or acquires resistance against ibrutinib. Here, to discover novel therapeutic targets, we present an unbiased loss-of-adhesion CRISPR-Cas9 knockout screening method to identify proteins involved in BCR-controlled integrin-mediated adhesion. Illustrating the validity of our approach, several kinases with an established role in BCR-controlled adhesion, including BTK and PI3K, both targets for clinically applied inhibitors, are among the top hits of our screen. We anticipate that pharmacological inhibitors of the identified targets, e.g. PAK2 and PTK2B/PYK2, may have great clinical potential as therapy for lymphoma and leukemia patients. Furthermore, this screening platform is highly flexible and can be easily adapted to identify cell adhesion-regulatory proteins and signaling pathways for other stimuli, adhesion molecules, and cell types.

Suggested Citation

  • Martin F. M. Rooij & Yvonne J. Thus & Nathalie Swier & Roderick L. Beijersbergen & Steven T. Pals & Marcel Spaargaren, 2022. "A loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29835-y
    DOI: 10.1038/s41467-022-29835-y
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    References listed on IDEAS

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    1. Jan A. Burger & Dan A. Landau & Amaro Taylor-Weiner & Ivana Bozic & Huidan Zhang & Kristopher Sarosiek & Lili Wang & Chip Stewart & Jean Fan & Julia Hoellenriegel & Mariela Sivina & Adrian M. Dubuc & , 2016. "Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
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