eLife (Mar 2022)

Confined migration promotes cancer metastasis through resistance to anoikis and increased invasiveness

  • Deborah Fanfone,
  • Zhichong Wu,
  • Jade Mammi,
  • Kevin Berthenet,
  • David Neves,
  • Kathrin Weber,
  • Andrea Halaburkova,
  • François Virard,
  • Félix Bunel,
  • Catherine Jamard,
  • Hector Hernandez-Vargas,
  • Stephen WG Tait,
  • Ana Hennino,
  • Gabriel Ichim

DOI
https://doi.org/10.7554/eLife.73150
Journal volume & issue
Vol. 11

Abstract

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Mechanical stress is known to fuel several hallmarks of cancer, ranging from genome instability to uncontrolled proliferation or invasion. Cancer cells are constantly challenged by mechanical stresses not only in the primary tumour but also during metastasis. However, this latter has seldom been studied with regards to mechanobiology, in particular resistance to anoikis, a cell death programme triggered by loss of cell adhesion. Here, we show in vitro that migrating breast cancer cells develop resistance to anoikis following their passage through microporous membranes mimicking confined migration (CM), a mechanical constriction that cancer cells encounter during metastasis. This CM-induced resistance was mediated by Inhibitory of Apoptosis Proteins, and sensitivity to anoikis could be restored after their inhibition using second mitochondria-derived activator of caspase (SMAC) mimetics. Anoikis-resistant mechanically stressed cancer cells displayed enhanced cell motility and evasion from natural killer cell-mediated immune surveillance, as well as a marked advantage to form lung metastatic lesions in mice. Our findings reveal that CM increases the metastatic potential of breast cancer cells.

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