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LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1

Author

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  • Alexander F. vom Stein

    (Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf
    University of Cologne
    University of Cologne)

  • Rocio Rebollido-Rios

    (Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf
    University of Cologne
    University of Cologne)

  • Anna Lukas

    (Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf
    University of Cologne
    University of Cologne)

  • Maximilian Koch

    (Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf
    University of Cologne
    University of Cologne)

  • Anton Lom

    (Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf
    University of Cologne
    University of Cologne
    Faculty of Medicine and University Hospital of Cologne)

  • Sebastian Reinartz

    (Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf
    University of Cologne
    University of Cologne)

  • Daniel Bachurski

    (Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf
    University of Cologne
    University of Cologne
    Faculty of Medicine and University Hospital of Cologne)

  • France Rose

    (University of Cologne
    Faculty of Medicine and University Hospital Cologne)

  • Katarzyna Bozek

    (University of Cologne
    University of Cologne
    Faculty of Medicine and University Hospital Cologne)

  • Ali T. Abdallah

    (University of Cologne)

  • Viktoria Kohlhas

    (Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf
    University of Cologne
    University of Cologne)

  • Julia Saggau

    (Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf
    University of Cologne
    University of Cologne)

  • Rebekka Zölzer

    (Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf
    University of Cologne
    University of Cologne)

  • Yue Zhao

    (University of Cologne)

  • Christiane Bruns

    (University of Cologne)

  • Paul J. Bröckelmann

    (Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf
    Faculty of Medicine and University Hospital of Cologne
    Max-Planck Institute for the Biology of Ageing)

  • Philipp Lohneis

    (Hämatopathologie Lübeck
    University of Cologne)

  • Reinhard Büttner

    (University of Cologne)

  • Björn Häupl

    (Johann Wolfgang Goethe University
    German Cancer Consortium (DKTK)
    German Cancer Research Center (DKFZ)
    Goethe University Frankfurt)

  • Thomas Oellerich

    (Johann Wolfgang Goethe University
    German Cancer Consortium (DKTK)
    German Cancer Research Center (DKFZ)
    Goethe University Frankfurt)

  • Phuong-Hien Nguyen

    (Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf
    University of Cologne
    University of Cologne)

  • Michael Hallek

    (Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf
    University of Cologne
    University of Cologne)

Abstract

Microenvironmental bystander cells are essential for the progression of chronic lymphocytic leukemia (CLL). We have discovered previously that LYN kinase promotes the formation of a microenvironmental niche for CLL. Here we provide mechanistic evidence that LYN regulates the polarization of stromal fibroblasts to support leukemic progression. LYN is overexpressed in fibroblasts of lymph nodes of CLL patients. LYN-deficient stromal cells reduce CLL growth in vivo. LYN-deficient fibroblasts show markedly reduced leukemia feeding capacity in vitro. Multi-omics profiling reveals that LYN regulates the polarization of fibroblasts towards an inflammatory cancer-associated phenotype through modulation of cytokine secretion and extracellular matrix composition. Mechanistically, LYN deletion reduces inflammatory signaling including reduction of c-JUN expression, which in turn augments the expression of Thrombospondin-1, which binds to CD47 thereby impairing CLL viability. Together, our findings suggest that LYN is essential for rewiring fibroblasts towards a leukemia-supportive phenotype.

Suggested Citation

  • Alexander F. vom Stein & Rocio Rebollido-Rios & Anna Lukas & Maximilian Koch & Anton Lom & Sebastian Reinartz & Daniel Bachurski & France Rose & Katarzyna Bozek & Ali T. Abdallah & Viktoria Kohlhas & , 2023. "LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36824-2
    DOI: 10.1038/s41467-023-36824-2
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