Nature Communications (Feb 2024)

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,
  • Camilla Raiborg

DOI
https://doi.org/10.1038/s41467-024-45558-8
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 22

Abstract

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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.