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

Eva Maria Wenzel, Nina Marie Pedersen, Liv Anker Elfmark, Ling Wang, Ingrid Kjos, Espen Stang, Lene Malerød, Andreas Brech, Harald Stenmark and Camilla Raiborg ()
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Eva Maria Wenzel: University of Oslo
Nina Marie Pedersen: University of Oslo
Liv Anker Elfmark: University of Oslo
Ling Wang: University of Oslo
Ingrid Kjos: University of Oslo
Espen Stang: Oslo University Hospital
Lene Malerød: University of Oslo
Andreas Brech: University of Oslo
Harald Stenmark: University of Oslo
Camilla Raiborg: University of Oslo

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45558-8

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