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

Eva Maria Wenzel1,2, Nina Marie Pedersen1,2, Liv Anker Elfmark1,2

  • 1Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.

Nature Communications
|February 10, 2024
PubMed

Insights

Cancer cells can transfer invasiveness to non-invasive cells via a soluble fragment of MT1-MMP (matrix metalloproteinase 14). This transfer is mediated by TKS4/5 proteins within acidic endosomes, promoting cancer cell invasion.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Overexpression of MT1-MMP (matrix metalloproteinase 14) is linked to increased cancer cell invasion.
  • The precise mechanisms by which MT1-MMP contributes to intercellular transfer of invasiveness are not fully understood.

Purpose of the Study:

  • To investigate how MT1-MMP-positive cancer cells induce invasiveness in MT1-MMP-negative cells.
  • To elucidate the role of TKS4 and TKS5 adaptor proteins in this process.

Main Methods:

  • Investigated the transfer of soluble MT1-MMP ectodomain between cancer cells.
  • Utilized techniques to study protein interactions within endosomes, including the role of pH and specific protein domains (PX domains).
  • Examined the formation and secretion of extracellular vesicles containing MT1-MMP ectodomain.

Main Results:

  • MT1-MMP-positive cells transfer an active ectodomain of MT1-MMP to non-invasive cells, rendering them invasive.
  • TKS4 and TKS5 are crucial for this transfer, facilitating ADAM-mediated cleavage of MT1-MMP within acidic endosomes.
  • The PX domains of TKS4/5 mediate interactions with MT1-MMP and phosphatidylinositol 3-phosphate, promoting MT1-MMP shedding and secretion via extracellular vesicles.

Conclusions:

  • TKS4/5 adaptor proteins are key mediators of intercellular transfer of cancer cell invasiveness.
  • ADAM-mediated shedding of MT1-MMP in acidic endosomes, facilitated by TKS4/5, is a novel mechanism for promoting cancer spread.
  • The shed MT1-MMP ectodomain acts as a soluble factor that converts recipient cells to an invasive phenotype.

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