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Intercellular transfer of cancer cell invasiveness via endosome-mediated protease shedding

Author

Listed:
  • Eva Maria Wenzel

    (University of Oslo
    Oslo University Hospital)

  • Nina Marie Pedersen

    (University of Oslo
    Oslo University Hospital)

  • Liv Anker Elfmark

    (University of Oslo
    Oslo University Hospital)

  • Ling Wang

    (University of Oslo
    Oslo University Hospital)

  • Ingrid Kjos

    (University of Oslo
    Oslo University Hospital)

  • Espen Stang

    (Oslo University Hospital)

  • Lene Malerød

    (University of Oslo
    Oslo University Hospital)

  • Andreas Brech

    (University of Oslo
    Oslo University Hospital
    University of Oslo)

  • Harald Stenmark

    (University of Oslo
    Oslo University Hospital)

  • Camilla Raiborg

    (University of Oslo
    Oslo University Hospital)

Abstract

Overexpression of the transmembrane matrix metalloproteinase MT1-MMP/MMP14 promotes cancer cell invasion. Here we show that MT1-MMP-positive cancer cells turn MT1-MMP-negative cells invasive by transferring a soluble catalytic ectodomain of MT1-MMP. Surprisingly, this effect depends on the presence of TKS4 and TKS5 in the donor cell, adaptor proteins previously implicated in invadopodia formation. In endosomes of the donor cell, TKS4/5 promote ADAM-mediated cleavage of MT1-MMP by bridging the two proteases, and cleavage is stimulated by the low intraluminal pH of endosomes. The bridging depends on the PX domains of TKS4/5, which coincidently interact with the cytosolic tail of MT1-MMP and endosomal phosphatidylinositol 3-phosphate. MT1-MMP recruits TKS4/5 into multivesicular endosomes for their subsequent co-secretion in extracellular vesicles, together with the enzymatically active ectodomain. The shed ectodomain converts non-invasive recipient cells into an invasive phenotype. Thus, TKS4/5 promote intercellular transfer of cancer cell invasiveness by facilitating ADAM-mediated shedding of MT1-MMP in acidic endosomes.

Suggested Citation

  • Eva Maria Wenzel & Nina Marie Pedersen & Liv Anker Elfmark & Ling Wang & Ingrid Kjos & Espen Stang & Lene Malerød & Andreas Brech & Harald Stenmark & Camilla Raiborg, 2024. "Intercellular transfer of cancer cell invasiveness via endosome-mediated protease shedding," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45558-8
    DOI: 10.1038/s41467-024-45558-8
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    References listed on IDEAS

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