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Title: Mechanotransduction in health and disease
Author: Chronopoulos, Antonios
ISNI:       0000 0004 6496 9689
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Physical forces regulate cellular behaviour and function during all stages of life. Mechanotransduction, the process by which cells convert mechanical stimuli into biochemical signalling events is central to a number of physiological and pathological processes. The first part of this work focuses on the effect of retinoid therapy on the mechanobiology of pancreatic cancer. Pancreatic cancer is characterised by a persistent activation of stromal fibroblasts, known as pancreatic stellate cells (PSCs), which can perturb the biomechanical homeostasis of the tumour microenvironment to favour tumour invasion. Using biophysical and biological techniques, we report that all-trans retinoic acid (ATRA), an active vitamin A metabolite restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-β)-mediated downregulation of actomyosin (MLC-2) contracility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models. We thus suggest that ATRA may serve as a stroma reprogramming agent for the treatment of pancreatic cancer. In the second part of this work, we focus on syndecan-4 (Syn-4) - a ubiquitous transmembrane proteoglycan receptor. We identify Syn-4 as a cellular mechanotransducer that tunes cell mechanics by eliciting a global mechanosignalling response. We outline a mechanotransduction model whereby localised tension on Syn-4 triggers a synergistic cell-wide activation of β1 integrins, in a PI3K-dependent manner, to subsequently activate the RhoA pathway and induce adaptive cell stiffening. Furthermore, syndecan-4 mediated mechanosensing is required for YAP activation and downstream changes in gene expression. We propose that this newly identified mechanotransductive ability of Syn-4 should have direct implications for the field of mechanobiology.
Supervisor: del Rio Hernandez, Armando Sponsor: European Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral