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?
  • https://www.scientificamerican.com/article/cancer-cells-can-t-proliferate-and-invade-at-the-same-time/
• Molecular basis of CIL is still lacking!

Personal Thoughts