Cancer Associated Fibroblast activation by nucleo-cytoplasmic force transduction (360G-Wellcome-105350_Z_14_A)

The mechanical properties of the extracellular microenvironment influence the behaviour of fibroblasts. Solid tumours often exhibit changes in the stromal extracellular matrix (ECM) and tumour growth in turn is directly regulated by the stroma and carcinoma-associated fibroblasts (CAFs). However, it is not clear how signals are transduced from the extracellular matrix to the nucleus of CAFs or how this influences global cellular processes such as transcription. We have dentified the existence of a novel force transduction pathway from adhesion sites to the nucleus that is able to regulate cell migration and is required for tension-dependent changes in transcription. We will compare the adhesion and mechanical transduction properties of normal tissue fibroblasts with CAFs to identify how the tumour microenvironment influences force transmission. The aims of this project are: - Analyse the nucleo-cytoplasmic force coupling-dependent adhesome of carcinoma-associated fibroblasts - Identify how nucleo-cytoplasmic force coupling influences cell-matrix adhesion properties and functions - Investigate how beta-PIX regulates nucleo-cytoplasmic force transduction in CAFs - Determine the role of CAF nuclear force modulation on transcription and tumour cell invasion