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Final Report Summary - MECPATH (Mechanical pathways in cells: from molecular mechanisms to cell function)

Mechanical forces transmitted between cells and their environment determine a wide range of processes in health and disease, including cancer, development, or wound healing. One of the main pathways of force transmission is through the transmembrane molecules integrins, which connect to the actin cytoskeleton through a set of adaptor proteins. The main objective of this project is to establish the role of those adaptor proteins in the mechanical communication of cells with their environment. During the first half of the project, we advanced significantly in this goal. First, we discovered that one of the main adaptor proteins linking actin to integrins, alpha-actinin, is responsible for force transmission and for the subsequent maturation of adhesions. Further, we showed that to carry out this role alpha-actinin competes for integrin binding with another adaptor protein, talin, providing a stepwise mechanism of force buildup and transmission (Roca-Cusachs et al., 2013, PNAS 110, E1361-E1370). Second, we unveiled how this force transmission is coupled to the properties of integrins to regulate cell response to a crucial tissue parameter, mechanical rigidity. In the context of breast cells, we determined that force application from adaptor proteins to integrins determines cell rigidity sensing by affecting the bond dynamics between integrins and the extracellular matrix. Further, we unveiled that the different bond properties of integrins found in healthy tissue (alpha5 beta1) and in malignant tissue (alphav beta6) lead cells to adapt optimally to rigidities associated with either soft healthy tissue or stiff malignant tissue (Elosegui-Artola et al., 2014, Nature materials 13:631-637).

In the second half of the project, we determined how the molecular properties under force of integrins and talin provide a molecular mechanism by which cells detect and respond to tissue rigidity, triggering the activation of the oncogene YAP. This provides a detailed description of a molecular mechanism of rigidity sensing, a long standing question in mechanobiology (Elosegui-Artola et al., 2016, Nat Cell Biol 18: 540-548). Additionally, we characterized how dynamic force application to cells affects the cellular membrane, leading to the formation of membrane invagination with specific shapes predicted by a mechanical model. Such membrane invaginations may then trigger downstream mechanotransduction processes (Kosmalska et al., 2015, Nat Commun 6: 7292). Finally, we determined how integration of force transmission across the length of several cells allows cell collectives to detect gradients in tissue rigidity, and to migrate directionally to stiff environments (Sunyer et al., 2016, Science 353: 1157-1161). This provides a robust mechanism of directional migration powered simply by mechanical balance.

In terms of career development, the fellow currently has obtained two compatible parallel appointments: one as assistant professor at the University of Barcelona (UB), and another as junior group leader at the Institute for Bioengineering of Catalonia (IBEC). The first position is scheduled to undergo tenure evaluation during spring 2017, and the second position was successfully tenured in June 2016. The fellow is also fully independent, and has established his own laboratory currently composed of two post-doctoral researcher, three Ph.D. students, and one master student. Significant funding has also been obtained from several sources, including the Spanish and Catalan governments, the EU (FET proactive, coordinator) and charity organizations. The fellow has also been selected as EMBO Young Investigator. Significant collaborations at the local, national, and international level have also been established with leading laboratories.

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