Introduction to session talk
Tissue regeneration, stem cells and cancer: roles of the mechanotransducers YAP/TAZ
Stefano Piccolo, Padua University, Italy
Stefano Piccolo studies how cells sense their environment and use this information to build and maintain tissues with specific form, size and function, and how these systems are corrupted in diseases. At the centerpiece of these events is the activity of the transcriptional coactivators YAP and TAZ. Enhanced YAP/TAZ activity is emerging as a hallmark of multiple human tumours. Stefano will discuss the cell and tissue-level mechanisms that lead to unrestrained YAP/TAZ activity, in turn essential for tumour formation and for tissue regeneration upon injury. He will also present new evidence on the function of YAP/TAZ in regulating the biology of normal somatic stem cell explanted from adult tissues.
CDK1 inhibition is the trigger for remodelling of adhesion complexes in G2 phase of the cell cycle
Professor Martin Humphries FMedSci, University of Manchester, UK
In most tissues, anchorage-dependent growth and cell cycle progression are dependent on the engagement of cells with extracellular matrices via integrin receptor adhesion complexes. In a highly conserved manner, cells disassemble adhesion complexes, round up, and retract from their surroundings prior to division, suggestive of a primordial link between the cell cycle machinery and the regulation of cell-extracellular matrix adhesion. In this talk, Martin Humphries demonstrates that CDK1, a promiscuous serine/threonine kinase and master regulator of the cell cycle, mediates this link. CDK1, in complex with cyclin A2, has an interphase role in promoting adhesion complex and actin cytoskeleton organisation, and it also mediates a large increase in adhesion complex area as cells transition from G1 into S. Adhesion complex area starts to decrease early in G2 and disassembly occurs several hours prior to mitosis. This loss requires elevated cyclin B1 levels and is caused by inhibitory phosphorylation of CDK1-cyclin complexes. The inactivation of CDK1, which prevents phosphorylation of its myriad substrates, is therefore the trigger that initiates remodelling of adhesion complexes and the actin cytoskeleton in preparation for rapid entry into mitosis.
The dark side of fibroblast force
Dr Danijela Matic Vignjevic, Institute Curie, France
Tumour microenvironment plays an important role in the tumour progression. It is made of extracellular matrix (ECM), blood vessels, immune cells and cancer-associated fibroblasts (CAFs). Besides biochemical signals, mechanical forces from microenvironment also play a role in tumour progression. CAFs have enhanced contractility and capacity to synthesize, deposit and crosslink ECM making stroma stiffer. Thus, by accumulating around the tumour, they could provide a physical barrier constraining tumour expansion. However, it has been shown that by exerting mechanical forces on the ECM, CAFs also enhance tumour invasion. These antagonistic roles of forces produced by CAFs in tumour progression will be discussed.
Endocytic control of mechanics, collective motion and cancer progression
Dr Giorgio Scita, IFOM, FIRC Institute of Molecular Oncology, Italy
Collective motility is ruled by both biochemical and physical interactions that cells establish among each other and with their environment. An emerging framework to interpret these interactions in unifying principles is the notion of cell jamming. During collective motility cells can flow like a fluid, but as density rises, the motion of each cell is constrained by the crowding due to its neighbours. At a critical density, motility ceases and collectives rigidify undergoing a liquid (unjammed)-to-solid (jammed) transition, herein referred to as UJT. This transition is thought to ensure proper development of barrier properties in epithelial tissues, but also to act as a tumour suppressive mechanism. The reverse, JUT might, instead, represent an alternative gateway to cell migration, enabling tissues to escape the caging imposed by the crowded cellular landscape of mature epithelia. The general validity of this physical framework and of JUT, however, remains to be verified. Even less understood is how cells control such phase transitions. In this talk, Giorgio Scita will address these issues and discuss whether the transition between “solid” and “liquid” locomotory states is an alternative or complementary gateway to epithelial-to-mesenchymal transition (EMT) to account for the plastic remodelling of epithelial tissues in physiology and pathology.
Cell collision geometry is critical for the emergence of extracellular matrix anisotropy
Dr Erik Sahai, Francis Crick Institute, London, UK
The organisation of the extra-cellular matrix (ECM) is crucial in determining both tissue structure and function. Many matrix proteins are organised into fibrillar structures with diameters in the range of 10-100nm and lengths in the range 10-100μm. Higher levels of organisation extending into the millimetre scale are also observed with aligned anisotropic matrices found in many tissues and pathologies, such as cancer and fibrosis. How such aligned ECM is generated is not well understood. Erik Sahai has undertaken a comprehensive survey of fibroblastic cells comparing those that generate highly aligned anisotropic matrices with those that don’t. His group has found that higher order alignment enables the coordination of traction forces and thereby millimetre scale collagen re-organisation. Detailed analysis of the emergence of aligned matrices reveals an unexpected role for cell collisions in coordinating ECM geometry. Further, combined RNAseq analysis reveals the transcriptional regulatory network that enable this behaviour.
Dr Chris Bakal, Institute of Cancer Research, UK
Dr Julia Sero, Institute of Cancer Research, UK