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ERC

ForceRegulation Report Summary

Project ID: 282051
Funded under: FP7-IDEAS-ERC
Country: United Kingdom

Final Report Summary - FORCEREGULATION (How force regulates cell function: a molecular and cellular outlook)

This project has allowed the establishment and consolidation of the Cellular and Molecular Biomechanics laboratory in the Department of Bioengineering at Imperial College London. This is a multidisciplinary research group that has created a unique technical platform, which simultaneously bridges fields that have not overlapped before in a single laboratory (http://biomechanicalregulation-lab.org/techoverview/). The high-resolution microscopy suite is central in this scaffold, comprising (i) an atomic force microscope (AFM) purpose built to study single molecule events, and (ii) a confocal microscope with TIRF and FRET capabilities that is integrated with magnetic tweezers and elastic pillar sensors. These techniques have been successfully used to investigate the roles of different mechanosensitive proteins in health and disease at both the cellular and molecular levels. For instance, we have combined single molecule studies with cellular approaches to demonstrate that the full tail of the talin molecule can be mechanosensitive. We have delineated a new mechanotransduction mechanism in talin through the interaction of the talin R8 domain with the deleted in liver cancer-1 protein (DLC1). This mechanically controlled talin-DLC1 interaction modulates events downstream of RhoA, a fundamental molecule in cell mechanics. This finding also provides another dimension to understand how the mechanical unfolding of proteins triggers alternative downstream events in cells. We have also shown that cell spreading and attachment are affected by the length of the tethers on the substrate to which the cell attaches. Though the prevailing concept was that cells mechanosense substrate rigidity, our results showed that in addition to stiffness, adhesive ligand tether length is another physical cue that cells can sense. Furthermore, we have shown that tissue stiffness sustains the perpetual activation of pancreatic stellate cells (PSCs), cells that drive the extensive fibrosis in the stroma of pancreatic cancer and promote cancer initiation and progression. We have elucidated a novel molecular mechanism by which ATRA (all trans-retinoic acid), a vitamin A metabolite, biomechanically reprograms PSCs, abolishing their ability to remodel the matrix to promote cancer cell invasion. In general, we expect that these discoveries can open new avenues for more applied research in academia and industry. The interaction of cells with their physical environment has profound implications for tissue engineering and the latest endeavours to mimic human organs for drug design (organ-on-a-chip).

Reported by

IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE
United Kingdom
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