Plasticity of cancer cell invasion and metastasis
Dr Peter Friedl, Radboud University Nijmegen Medical Centre, The Netherlands, and The University of Texas, MD Anderson Cancer Center, USA
Cancer cell migration is a plastic and adaptive process generating molecular and physical heterogeneity of migration mechanisms and metastatic routes, including single-cell and collective metastasis. When monitored in vivo using intravital multiphoton microscopy, tissue microniches provide invasion-promoting tracks that enable collective migration along tracks of least resistance. In regions of tissue confinement, invading cancer cells undergo a jamming transition towards collective migration and circulate as both individual cells and multicellular clusters for collective organ colonisation. Using multi-targeted interference with integrin adhesion systems, conversion from collective invasion to amoeboid single-cell dissemination followed by increased rates of lung colonisation was detected. Similar amoeboid dissemination was induced by hypoxia or stabilisation of hypoxia-inducible factor (HIF). The data suggest that metastatic cancer cells can undergo physicochemical reprogramming in response to encountered tissue environments, and thereby balance cell-intrinsic adhesion and mechanocoupling with encountered cues. Dissecting the microenvironmental determinants underlying individual-to-collective plasticity, and vice versa, will enhance to derive combined “antimigration” and cytotoxic therapies and combat metastatic transitions.
The molecular clutch model as a framework to understand integrin-mediated mechanotransduction
Dr Pere Roca-Cusachs, Institute for Bioengineering of Catalonia, Spain
Cell proliferation and differentiation, as well as key processes in development, tumorigenesis, and wound healing, are strongly determined by the physical properties of the extracellular matrix (ECM). In this talk, Pere Roca-Cusachs’ approach combining molecular biology, biophysical measurements, and theoretical modelling to understand matrix rigidity sensing will be addressed. The roles of the properties under force of integrin-ECM bonds, and of the adaptor protein talin, will be discussed. This sensing can be understood through a computational molecular clutch model, which can quantitatively predict the role of integrins, talin, myosin, and ECM receptors, and their effect on cell response. Finally, it will be argued how this molecular clutch framework can explain cell sensing not only of substrate rigidity, but also of ECM spatial distribution of ligands, and how both rigidity and spatial sensing can be understood through the general principle of cell sensing of force loading rates.
Crosstalk between fibroblastic stroma and leukocytes controls contractility and matrix remodelling
Dr Sophie Acton, MRC-Laboratory for Molecular Cell Biology, University College London, UK
Sophie Acton’s interests lie in the communication between different cell types of the immune system, specifically the mechanisms controlling cellular trafficking, multicellular organisation and lymphoid organ architecture. The Acton lab uses the lymph node as their model system for investigating these processes. The lymph node is a highly organised and tightly controlled environment. The dynamic nature of lymph node swelling and contraction is critical to all immune responses and is not well understood. The group wants to understand the processes involved in lymph node swelling/expansion, and how these changes are coordinated. The interplay between immune cells and non-haematopeotic stromal cells is key to this process. There are many parallels between the cells interacting in the lymph node during an immune response, and the interactions happening in a tumour. Many of the same or similar cell types are present but a tumour is a hugely disorganised mess, and even worse, every tumour is different. One of the major benefits of their research is that they can use the lymph node model to both understand immunity, but also take those findings and apply that knowledge to the same cells in tumours, helping to understand cancer better, and hopefully find ways to harness our immune system to fight and destroy tumours.
A unified pathway linking microtubules, myosin-II filaments and integrin adhesions
Professor Alexander Bershadsky, Mechanobiology Institute, National University of Singapore, Singapore, and Weizmann Institute of Science, Israel
The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, Alexander Bershadsky shows that the effects of microtubules on two major types of cell-matrix adhesions, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin-IIA filaments. Myosin-IIA filaments, augmenting the focal adhesions and disrupting the podosomes, are indispensable effectors in the microtubule-dependent regulation of integrin-mediated adhesions. Myosin-IIA filament assembly depends on Rho activation by the RhoGEF, GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capturing by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the myosin-IIA filaments. Subsequent actomyosin reorganisation then remodels the focal adhesions and podosomes, closing the regulatory loop.
Assessing the tensional state of fibronectin fibres in cancer stroma
Professor Viola Vogel, ETH Zürich, Switzerland
Major transformations of extracellular matrix (ECM) accompany cancer progression, yet it remains poorly understood whether and how the ECM orchestrates the deterioration of healthy to pathological tissues. These processes are regulated by a complex interplay of cells with their ECM, whereby the biochemical composition as well as the physical features of ECM are well recognised to regulate diverse cell functions. Spatial mapping of the strain of ECM fibrils is crucial to learn how fibre stretching correlates with cell signalling events and disease progression. Progress was hampered though due to the lack of nanoprobes capable of sensing cell generated forces or the molecular strains at the tissue level. The Vogel lab thus took advantage of the evolution of bacterial adhesins that specifically target FN with high affinity, but only the relaxed but not stretched fibres, and exploited them to map the strain of ECM fibrils within histological cryosections of tumour stroma and in living animals. Spatial proximity analyses with other biomarkers provide first insights into functional correlations as further discussed in the presentation.