Periodic Report Summary 1 - MODSIGN (Modification of receptor tyrosine kinase signalling during tumour cell migration) Cancer is a major socio-economic problem in EU, with approximately 2.5 million cases diagnosed and 1.2 million deaths every year, and an annual estimated cost of 15 billion € for cancer therapy. Understanding the molecular mechanisms underlying cancer progression have revolutionized the field of targeted therapies, generating a growing number of inhibitors approved for use in the clinic. In particular, drugs targeting receptor tyrosine kinases (RTKs) have been successful. Although several of these therapies showed initial benefits, a recurring problem in cancer management is development of secondary mutations of the targeted proteins, causing drug resistance. To counteract this, there is an urgent need to identify the next generation of drug targets required to create the second line therapies that are critically needed. The specific aim of this proposal is to elucidate the molecular networks that modify RTK signalling output during tumour progression to metastatic disease, with the aim of identifying network nodes that can subsequently be targeted for drug development.The goal of this proposal is to investigate the molecular mechanisms whereby RTK signalling output is modified, and how they are altered during cancer progression to metastatic disease. In vivo, tumour cells are simultaneously exposed to signals initiated by a variety of oncogenes, cytokine receptors and adhesion molecules, and it is the integrated signals that determine the cellular phenotype. Realizing that cancer is a disease of networks, this proposal investigates signal integration at the level of regulating RTK internalization and trafficking. Specifically, the proposed research will significantly expand the understanding of the intersection between two interlinked networks that regulate RTK signalling, i.e. PTPs and endocytic trafficking. The ultimate aim of this line of research is to identify novel drug targets that can subsequently be exploited by the European pharmaceutical industry.