Final Report Summary - T3NET (Tissue Transmigration Training Network) Cardiovascular and cancer-related diseases are the leading causes of human mortality and disability. The underlying mechanisms originate in three fundamental processes: cell adhesion, migration, and modulation/degradation of the extracellular matrix (ECM), which together determine pathological tissue invasion and remodelling. Our ability to understand these processes has been greatly enhanced in recent years through advances in cell biology, mechanobiology, molecular biology and microscopic imaging techniques. These approaches are revealing new details of how cells invade and degrade ECM, especially through protruding cell structures known as podosomes or invadopodia, which mediate cell invasiveness in physiological and pathological contexts, respectively.The Tissue Transmigration Training Network (T3Net) has been supported for 4 years by the European Union through its FP7 PEOPLE programme (Marie Curie Actions), to provide training to 14 young scientists (12 PhD students, and 2 post-doctoral researchers) working on studies of cell adhesion, migration and invasion. The network of 8 T3Net partners across 7 countries was coordinated by Universitätsklinikum Hamburg Eppendorf in Germany. It involves leading research groups working in the field of cell invasion and migration, as well as a biotechnology SME company Excellness SA. As the FP7-PEOPLE programme promotes international mobility, each partner has recruited young scientists (T3Net fellows) from another country, and trained them through an individual research project and a programme of joint training activities: meetings, training centers, courses and secondments. T3Net has also benefited from co-operation with Associated Partners in industry (AstraZeneca, UK and IDEA Biomedical, Israel) and the Open University, UK for complementary skills training. Of the T3Net fellows, 12 have been recruited as PhD students, and 2 as post-doctoral researchers. The individual research projects of the T3Net fellows have made significant progress in our understanding of cell invasion and ECM degradation by various invasive cell types. To date, 43 peer reviewed articles have been published with T3Net support. More work is in progress and many reports are yet to be published; we can highlight the following achievements:• Using molecular biology, progress has been made in understanding how specific cell membrane lipids and the protein Fdg1 regulate the formation of invadopodia, the structures involved in degradation of ECM by cancer cells. Using similar approaches, the mechanisms of podosome formation in dendritic cells have been investigated, focussed on the protein WASP.• Proteomics and gene expression have been used to newly identify genes and proteins involved in formation of podosomes in macrophages and bone osteoclasts and also in the regulation of ECM degradation. Selected proteins, including LSP-1 and MMP-12 are now being studied further to understand their functions in both normal and diseased cells.• The protein TGFbeta1 has a key role in cell differentiation and growth, and stimulates podosome formation. T3Net have investigated the specific TGFbeta receptors involved in podosome formation, and how treatment with TGFbeta1 influences podosome structure both in vitro and in vivo. • Two industrially focused projects have exploited the novel cell culture substrates of Excellness SA, that mimic the physical properties of ECM much better than conventional plastic culture dishes. The effect of physical stress within ECM on TGFbeta release has been investigated, and the processes causing stem cells to differentiate into myofibroblasts. These projects have potential for eventual applications in wound healing and regenerative medicine respectively.• Three projects have employed advanced nanopatterning and imaging methods to observe cell adhesion and migration. The effects of artificial substrate patterning on the adhesive “sealing zone” of osteoclasts has been observed, and the individual and collective invasion of cancer cells through 3D ECM both in vitro and in vivo. The function of specific proteins involved in ECM degradation by cancer cells has been investigated in these models, aided by advanced imaging and biophysical techniques.Most of the T3Net fellows have undertaken part of their project in a secondment visit to another partner. T3Net has organised annual open symposia for the fellows to share and discuss their results, including the 2011 symposium held alongside the 4th Invadosome meeting in Madrid, and the 2012 symposium at AstraZeneca in the UK that included business-related sessions. Joint training courses in Israel and the Netherlands have provided hands on experience in automated microscopy, cell mechanics and intravital 2-photon imaging. Finally the T3Net fellows had access to complementary skills training including an on-line study skills course, plus courses at their host institutions.T3Net has reached its target for the number of young scientists to be trained, has reinforced multidisciplinary collaboration between European scientists, and has delivered a cohort of well connected young research professionals trained in advanced methods for biomedical science and well equipped to pursue an international career in academic research or industry. T3Net fellows will continue to publish their findings through papers in scientific journals and at major conferences in Europe, such as the upcoming 5th Invadosome meeting in Nijmegen (Oct. 2013) and elsewhere. The scientific results of T3Net increase our basic understanding of cell invasion, migration and interaction with ECM in both healthy and diseased cells, and will contribute eventually to improved diagnosis and treatments for cancer and cardiovascular disease, and other medical applications.The T3Net website can be accessed at http://www.t3net-itn.org. It is regularly updated with news, publications, press releases and events. It also features a section with summaries of the results written to help the general public understand the research undertaken in the project.For more information please contact the T3Net Project Coordinator: Prof. Dr. Stefan Linder, UKE, Hamburg, Germany (s.linder@uke.de)
