The front and rear of collective cell migration

Mayor, Roberto, and Sandrine Etienne-Manneville. “The front and rear of collective cell migration.” Nature Reviews Molecular Cell Biology (2016).

Summary & Highlights

  • Collectively migrating group of cells is that it migrates more efficiently than if cells were isolated
  • Cells become leaders in response to
    external cues, which include the ECM, soluble factors and neighbouring cells
  • Moreover, ECM fibres control the migration of multi- cellular streams in vivo by providing directional cues
  • Beta1-integrains
    • Recruitment & activation of CDC42/RAC through adaptor proteins associated with GEFs such as SCRIB, BPIX or PAR3 and TAMI; and intracellular kinase FAK and SRC
    • Downstream effectors: SCAR-WAVE complex
  • Polarized intracellular organization of the leader cells promotes positive feedback loops and contributes to the stabilization of the polarized cell state
  • When large sheets/clusters migrating, leader cells are linked together by adhesive structures (adherens junction)
  • Adherens Junctions
    • Cadherins = main transmembrane component, control actin and microtubule via catenins
    • Anisotropic distribution of adherens induces anisotropic distribution of focal adhesions
    • Transverse acto-myosin cables contribute to multicellular actin network
    • Continuous acto-myosin drive retrograde flow along lateral sides
      • Treadmilling! Cadherens recycled toward leading edge
  • Transmission of information to the followers
    • Leader cells not only explore the tissue environment and identify the migration path, they also significantly contribute to the directed migration of the followers.
    • ECM secretion of leader cells can be different
    • Mechanotransducers undergo a conformational change upon stretching, revealing new protein-interaction domains and inducing biochemical signalling, which in turn can modulate the strength of adhesion.
    • **Merlin is involved in mechanotransduction during collective migration
      • Translocates from cell-cell contact to cell cytoplasm to support polarization of RAC1 & lamellipodium formation
    • Antagonistic relationship between cadherin-mediate junctions & integrin-based adhesions
    • Followers can directly participate in generating pulling forces far away from leader cells; long-range transmission
    • Followers play an important role
      • One role is phenomenon of contact inhibition of locomotion (CIL)
      • Two migrating cells, upon collision, halt their forward locomotion by collapsing protrusions at the site of contact and establishing protrusions away from each other
      • 1. Sense contact with other cells
      • 2. Signal transmitted from surface to inside cell
      • 3. Intracellular signals drive protrusion collapse at cell contact & repolarize with new protrusions away from cell contract
        • Cadherins, ephrins & EPH receptors, plane planar cell polarity pathway
    • Chemotaxis– source and sink of chemical
      • Cells can generate their own gradient!

Future Questions

  • Are the links that leader cells make with each other different from the links formed between leader cells and non-leader?
  • Do multiply attached leader cells generate more forces?
  • Is the ECM secreted by leader cells different from follower cells?
  • Define role of leader and followers in collective cell migration!
  • Why doesn’t CIL occur when invadopodia migrate out?
  • Do cells with invadopodia divide?
  • Molecular basis of CIL is still lacking!

Personal Thoughts

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