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Mechanobiology of Disease
Thursday Speaker Abstracts
35
Force Loading Explains How Substrate Rigidity and Ligand Nano-Distribution Regulate
Cell Response.
Roger Oria
1,2
, Tina Wiegand
3,4
, Jorge Escribano
5
, Alberto Elosegui-Artola
1
, Juan José Uriarte
2
,
Daniel Navajas
1,2
, Xavier Trepat
1,6
, Jose Manuel Garcia-Aznar
5
, Elisabetta Ada Cavalcanti-
Adam
3,4
,
Pere Roca-Cusachs
1,2
.
1
Institute for Bioengineering of Catalonia, Barcelona, Spain,
2
University of Barcelona,
Barcelona, Spain,
3
Max-Planck-Institute for Medical Research, Heidelberg,
Germany,
4
University of Heidelberg, Heidelberg, Germany,
5
University of Zaragoza, Zaragoza,
Spain,
6
Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
Processes in development, cancer, and wound healing are determined by the rigidity and ligand
density of the extracellular matrix (ECM). ECM rigidity and ligand density are first probed and
detected via integrins, transmembrane proteins that link the ECM to the actin cytoskeleton.
Current understanding establishes an upper limit of 70nm spacing between integrins bound to
ligands on glass surfaces for appropriate clustering and subsequent formation of focal adhesions
(FAs). However, the mechanism behind this limit, and its regulation by rigidity, remain largely
unknown. Here, we developed a tunable rigidity substrate with controllable ligand spacing and
distribution at the nanometer scale. In response to rigidity, we counterintuitively found that FA
growth in breast myoepithelial cells was favored as ligand spacing increased from 50 to 100nm.
In addition, disordering the distribution of ligands while keeping their density and average
spacing constant triggered FA growth at lower rigidities and drastically increased their length.
Further, we found that FAs collapse by decreasing their length above a rigidity threshold.
Combined with measurements of traction forces and actin flows, these results match qualitatively
with a molecular clutch model. This model predicts that substrate rigidity and ligand density
affect adhesion formation by regulating integrin-ECM bond force loading, which in turn controls
ensuing mechanosensing events. Taken together, our findings suggest a force-dependent
mechanism which explains FA formation, growth and collapse in response to rigidity and ligand
density. Such a mechanism may mediate cell response to the changes in ECM density and
rigidity that occur during the progression of breast cancer.