8th Annual Symposium
Physics of Cancer
October 4-6, 2017
|PoC - Physics of Cancer - Annual Symposium|
Mapping cadherin-dependent cell adhesion and elasticity changes in tissue explants during the transition from collective to single-cell migration
Karlsruhe Institute of Technology, Wolfgang-Gaede-Str. 1a, 76137 Karlsruhe, Germany
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During development neural crest cells (NCs) undergo epithelial-to-mesenchymal transition and switch from cooperative to single-cell migration, a process which has been compared to cancer cell detachment during metastasis. Here we have used atomic force microscopy (AFM) to investigate adhesive and mechanical changes associated with cell dissociation from cohesive NC explants. AFM-based single-cell force spectroscopy revealed a uniform distribution of cell-cell adhesion forces within tissue explants, including semi-detached leader cells in the process of delaminating from the explant edge, suggesting that cell dissociation does not require prior weakening of cell-cell contacts. However, mapping NC sheet elasticity demonstrated strongly reduced cell stiffness in semi-detached leader cells compared to neighbouring cells in the NC sheet periphery. Reduced leader cell stiffness coincided with enhanced cell spreading and high substrate traction, indicating a possible mechano-regulation of leader cell delamination. In support, reducing cell tension by inhibiting actomyosin contractility induces rapid spreading, possibly maximizing cell-substrate interactions as a result. Depletion of cadherin-11, a classical cadherin with an essential role in NC migration and substrate adhesion, prevented the tension reduction necessary for NC spreading, both in individual cells and at the edge of explanted sheets. In contrast, overexpression of cadherin-11 accelerated spreading of both individual cells and delaminating leader cells. As cadherin-11 expression increases strongly during NC migration, this suggests an important role of cadherin-11 in regulating cell elasticity and spreading at later stages of NC migration. We therefore propose a model in which high tension at the cell sheet periphery prevents premature spreading and delamination during early stages of NC migration, while a cadherin-11-dependent local decrease in cell tension promotes leader cell spreading and delamination at later stages of migration. Cadherin-11 is also frequently upregulated in invasive breast cancer, raising the intriguing possibility that cadherin-11 plays similar roles in human tumour progression.