Physical limits in cell migration identified

Wolf, Katarina

Friedl, PeterA hallmark of tumor progression is the invasive penetration of cancer cells into healthy tissues. Tissue-directed proteases, in particular MT1-MMP, promote tumor invasion, however debate was ongoing between different labs whether proteases are mandatory or dispensable for cancer cell dissemination.


In a joint collaboration between previous opponents, Katarina Wolf and Peter Friedl (NCMLS) together with the group of Steven Weiss (Ann Arbor, Michigan) now provide a unified concept which resolves controversy. They show that the role of proteases depend upon the space available in the tissue. Cancer cells can migrate forward without proteases when ECM pores are large enough to accommodate the cell. For this, researchers used common three-dimensional collagen models that were subsequently modulated in pore size. Conversely, very small pores limit cell translocation, particularly because of limited deformability of the nucleus. With smaller diameters in the absence of MT1-MMP, cells were unable to deform their nucleus in pores and got stuck (minimal pore diameter of 2-3 micrometer; 'physical limit'). The presence of proteases lead to "opening" of pores and cancer cell invasion was maintained. The next step will be to validate gap dimensions in connective tissues and to test whether these will proof too small to allow tumor passage in the presence of protease inhibitors in vivo. To demonstrate a general principle of migration physics, other cells were studied, including T-blasts with mononuclear shape migration (limits around 2-3 micrometer) and polymorphonuclear neutrophils (limit: 1 micrometer). As rule of thumb, cell compressibility was universal, with 1/10 of the nuclear cross section as maximum. Collectively, these data and concepts will serve as a multiparameter matrix integrating different cell migration types in health and disease.

The Journal of Cell Biology published these results as cover story on June 24:
Physical limits of cell migration: Control by ECM space and nuclear deformation and tuning by proteolysis and traction force.
Katarina Wolf, Mariska te Lindert, Marina Krause, Stephanie Alexander, Joost te Riet, Amanda L. Willis, Robert M. Hoffman, Carl G. Figdor, Stephen J. Weiss, Peter Friedl


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