09:00-09:30
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
Abstract
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.
Show speakers
Dr Peter Friedl, Radboud University Nijmegen Medical Centre, The Netherlands, and The University of Texas, MD Anderson Cancer Center, USA
Dr Peter Friedl, Radboud University Nijmegen Medical Centre, The Netherlands, and The University of Texas, MD Anderson Cancer Center, USA
-
Dr Peter Friedl, Radboud University Nijmegen Medical Centre, The Netherlands, and The University of Texas, MD Anderson Cancer Center, USA
-
Dr Peter Friedl, Radboud University Nijmegen Medical Centre, The Netherlands, and The University of Texas, MD Anderson Cancer Center, USA
- Membership status unknown
- No primary institution
Dr Friedl received his MD degree from the University of Bochum (1992) and the PhD degree from the McGill University, Montreal (1996). Since 2007 he has been directing the Microscopical Imaging Centre of the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, and since 2011 has held a joint-faculty position at the University of Texas MD Anderson Cancer Center, Houston, Texas, for preclinical intravital imaging of cancer lesions and their response to molecular targeted and immunotherapy. His research interest is the mechanisms and plasticity of cell migration in immune regulation and cancer metastasis, with emphasis on cell-matrix adhesion, pericellular proteolysis and cell-cell communication during migration. His laboratory identified pathways determining diversity and plasticity of cell migration, collective cancer cell invasion, and the contribution of migration pathways to immune defense and cancer resistance. His discoveries have provided a nomenclature for the different types of cell migration and their roles in building and (re)shaping tissue, with emphasis on inflammation, regeneration and cancer. His therapeutic preclinical studies focus on the intravital visualization of niches and mechanisms and strategies to overcome therapy resistance.
09:30-10:00
The molecular clutch model as a framework to understand integrin-mediated mechanotransduction
Dr Pere Roca-Cusachs, Institute for Bioengineering of Catalonia, Spain
Abstract
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.
Show speakers
Dr Pere Roca-Cusachs, Institute for Bioengineering of Catalonia, Spain
Dr Pere Roca-Cusachs, Institute for Bioengineering of Catalonia, Spain
Pere Roca-Cusachs obtained his PhD in cellular biophysics in 2007 from the Medical School at the University of Barcelona. He then worked in the lab of Professor Michael Sheetz (Department of Biological Sciences, Columbia University) as a post-doctoral researcher until 2011. In 2011, he joined the University of Barcelona, where he is now an associate professor. In 2012, he obtained a joint position as group leader at the Institute for bioengineering of Catalonia (IBEC). He is a recipient of the EMBO Young Investigator Award. The research of his group focuses on unravelling the physical and molecular mechanisms by which cells detect and respond to mechanical force.
10:00-10:30
Crosstalk between fibroblastic stroma and leukocytes controls contractility and matrix remodelling
Dr Sophie Acton, MRC-Laboratory for Molecular Cell Biology, University College London, UK
Abstract
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.
Show speakers
Dr Sophie Acton, MRC-Laboratory for Molecular Cell Biology, University College London, UK
Dr Sophie Acton, MRC-Laboratory for Molecular Cell Biology, University College London, UK
Dr Acton studied Pharmacology at the University of Bath, before spending a year working at Millenium Pharmaceuticals. She then started a PhD at the Cancer Research UK London research institute, studying mechanisms of metastasis in melanoma. Her first postdoc position was located at the Dana-Farber Cancer Institute at Harvard Medical School, working on mechanisms of dendritic cell migration. For her second postdoctoral training, back in London with Caetano Reis e Sousa, she worked on mechanisms of lymph node expansion supported by a Henry Wellcome Postdoctoral Fellowship. Dr Acton started her Stromal Immunology group at the MRC Laboratory for molecular cell biology at UCL in 2016, and her lab now is funded by Cancer Research UK and the European Research council.
11:00-11:30
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
Abstract
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.
Show speakers
Professor Alexander Bershadsky, Mechanobiology Institute, National University of Singapore, Singapore, and Weizmann Institute of Science, Israel
Professor Alexander Bershadsky, Mechanobiology Institute, National University of Singapore, Singapore, and Weizmann Institute of Science, Israel
-
Professor Alexander Bershadsky, Mechanobiology Institute, National University of Singapore, Singapore, and Weizmann Institute of Science, Israel
-
Professor Alexander Bershadsky, Mechanobiology Institute, National University of Singapore, Singapore, and Weizmann Institute of Science, Israel
- Membership status unknown
- No primary institution
Alexander Bershadsky graduated from the Moscow State University with an MSc in mathematics and obtained his PhD in Cell Biology at the Cancer Research Center of the Russian Academy of Medical Sciences, where he continued to work until 1992. He published a book “Cytoskeleton” (1988, Plenum Press) together with J.M. Vasiliev. In 1992, Bershadsky moved to Israel and joined the Weizmann Institute of Science where he served sequentially as assistant, associate, and full professor, and is now (since 2017) a professor emeritus. Whilst at the Weizmann Institute, the Bershadsky laboratory was among the first to study the adhesion-dependent cell mechanosensitivity and microtubule-driven control of integrin-mediated adhesions. In 2009, he joined the Mechanobiology Institute (MBI) at the National University of Singapore where he currently holds a full-time position of Principal Research Scientist/Research Professor. Bershadsky’s research interests include cytoskeleton dynamics and self-organization, and the crosstalk between the cytoskeleton and cell adhesion.
11:30-12:00
Assessing the tensional state of fibronectin fibres in cancer stroma
Professor Viola Vogel, ETH Zürich, Switzerland
Abstract
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.
Show speakers
Professor Viola Vogel, ETH Zürich, Switzerland
Professor Viola Vogel, ETH Zürich, Switzerland
Viola Vogel is a Professor in the Department of Health Science and Technology heading the Laboratory of Applied Mechanobiology at the ETH Zürich, Switzerland. Trained as a Physicist and with her graduate research conducted at the Max-Planck Institute for Biophysical Chemistry, she spent two years as postdoctoral fellow at the University of California Berkeley. As faculty member, she joined the Department of Bioengineering at the University of Washington/Seattle in 1990 and moved there through the ranks to Full Professor. She was the Founding Director of the Center for Nanotechnology at the University of Washington (1997-2003) prior to her move to Switzerland in 2004, where she initially joined the Department of Materials. She serves on various advisory boards worldwide and has received major honors and awards, including the Otto-Hahn Medal of the Max-Planck Society 1988, the “First Award” from the Institute of General Medicine (National Institutes of Health USA, 1993-98), the Julius Springer Prize 2006 for Applied Physics, the ERC Advanced Grant (European Research Council 2008-13), the International Solvay Chair in Chemistry Brussels 2012, and an Honorary Degree Doctor of Philosophy from Tampere University, Finland 2012. She also served as a Rapporteur for the Max-Planck Society, Physical-Chemical Technical Division (2012-2013), as Panel Member Representing the European Research Council at the World Economic Forum in Davos (2013), as Jury Member for the Queen of Elizabeth Prize for Engineering (2015), and is a Member of the World Economic Forum Global Agenda Council in Nanotechnology (2014-2016).
She exploits nanotechnology tools to decipher how bacteria and mammalian cells and micro-tissues exploit mechanical forces to recognize and respond to material properties and their native environments. Her discoveries in single molecule and cell mechanics and how protein stretching switches their function, as well as in the field of mechanobiology have a wide range of technical and medical implications. In collaboration with clinicians, several technologies are currently carried towards preclinical studies.