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Gráczer Éva Laura

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Gráczer Éva Laura
Regulation of actin cytoskeleton dynamics through adhesion-molecule-mediated mechanotransduction

Aug 29 - kedd

15:30 – 17:00

I. Poszterszekció

P08

Regulation of actin cytoskeleton dynamics through adhesion-molecule-mediated mechanotransduction

Éva Gráczer, Laura Harsányi, Antónia Fülöp, Katalin Pászty and Andrea Varga

Semmelweis University, Department of Biophysics and Radiation Biology

Endothelial cells are continuously exposed to external forces. In addition, during inflammation or metastasis a leukocyte or a cancer cell can exert tension on the endothelial monolayer. Change in tension is sensed by cell adhesion molecules, such as ICAM-1 or PECAM-1, and is translated to specific cellular responses, such as actin reorganization, in a process called mechanotransduction. To model leukocyte or cancer cell mediated mechanotransduction, we used magnetic beads coated with an antibody against a specific adhesion molecule. After adhesion of the beads, we applied a continuous force (about 40 pN) with a permanent magnet on the endothelial monolayer and followed reorganization of the actin cytoskeleton by confocal microscopy. We have found that during PECAM-1-mediated mechanotransduction adhesion increased peripheral actin ring formation, which was followed by stress fiber formation upon application of force. VE-cadherin junctions were subsequently reorganized, weakening cell-cell junctions. Thus, the force applied by a cancer cell might help its transmigration by weakening endothelial cell-cell junctions. At the same time, the strength of cell-extracellular matrix (ECM) adhesion was increased, which might play a role in the regulation of cell-cell adhesion. During inflammation on the apical side of endothelial cells filopodia-like protrusions are formed, which help not only in the adhesion of immune cells, but also guide them where to pass the endothelial monolayer. We have found that adhesion through ICAM-1 increases the size of these filopodia, and their size is decreased upon force application. We could also visualize filopodia formation during the transmigration step of A375 melanoma cells. The molecular details of the regulation of filopodia size are not known and we propose that the activity of the Yes-associated protein, YAP might play a role. Our integrative biomechanical and cell signaling approach might reveal new targets to inhibit metastasis.

Acknowledgment

The research was supported by NKFIH/OTKA FK-132144 grant (A.V.) and by the Hungarian Academy of Sciences (Bolyai János Fellowship to A.V. and KGYNK 2023-45 Fellowship to É.G.).