Mechanisms coupling the cell cycle to cell adhesion at mitosis

In many tissues, an extreme increase in stromal elasticity makes a significant non-cell autonomous contribution to tissue function. The causes of this response and the consequent effects of high elasticity on cell phenotype are pivotal to an understanding of the biology of the tissue, but the area is under-explored. The specific focus of this proposal is to determine how stromal elasticity drives tumour cell proliferation, and two central hypotheses will be tested: first, that stromal elasticity is linked to the checkpoint-dependent regulation of cell cycle progression in normal pancreatic cells; and, second, that pancreatic tumour cells acquire mechanisms to evade this control. Building on our knowledge base of adhesion signalling and the specialist methodologies that we have pioneered over the past decade, we will establish original techniques for performing global analyses of adhesion signalling in three-dimensional pancreatic organoids, define the effects of varying extracellular elasticity on cell cycle progression, elucidate the underlying mechanisms, and pinpoint how mechanosensing varies between normal and tumour cells.