2. Academic Validation
  3. A loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways

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

  • Nat Commun. 2022 Apr 19;13(1):2136. doi: 10.1038/s41467-022-29835-y.
Martin F M de Rooij  # 1 2 3,  Yvonne J Thus  # 1 2 3,  Nathalie Swier 1 2 3,  Roderick L Beijersbergen 4 5,  Steven T Pals 1 2 3,  Marcel Spaargaren 6 7 8
Affiliations

Affiliations

  • 1 Department of Pathology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
  • 2 Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.
  • 3 Cancer Center Amsterdam (CCA), Cancer Biology and Immunology - Target & Therapy Discovery, Amsterdam, The Netherlands.
  • 4 Division of Molecular Carcinogenesis and Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands.
  • 5 NKI Robotics and Screening Center and Genomics Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands.
  • 6 Department of Pathology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands. marcel.spaargaren@amsterdamumc.nl.
  • 7 Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands. marcel.spaargaren@amsterdamumc.nl.
  • 8 Cancer Center Amsterdam (CCA), Cancer Biology and Immunology - Target & Therapy Discovery, Amsterdam, The Netherlands. marcel.spaargaren@amsterdamumc.nl.
  • # Contributed equally.
PMID: 35440579 DOI: 10.1038/s41467-022-29835-y
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.

Figures
Products