Cell migration in tumorigenesis and metastasis
Cell migration is fundamental to immunosurveillance and inflammation but also to tumor invasion and metastatic dissemination. Chemokines and their receptors play a central role in positioning immune and tumor cells with spatiotemporal precision. In the multi-step extravasation of circulating cells, chemokines trigger their arrest to the vascular endothelium, then make them move across the vascular wall and along surface-bound chemokine gradients to their destination. In the immune system, this is relevant to homeostatic recirculation of lymphocytes through lymphatic tissues as well as to recruitment of leukocytes to tissues during acute or chronic inflammation. In cancer, in addition to migration, chemokines also promote tumor cell proliferation and survival, and contribute to the formation of metastatic niches. Thus expression of chemokine receptors on circulating immune or tumor cells is critical to coordinate complex tissue responses. In addition to chemokines a number of factors (e.g. HGF or Ang2) have been recognized to exert chemotactic activity. In this ProDoc Research Module (RM) three PhD students will work on complementary and interlaced projects dedicated to address the roles of chemotactic factors and their cognate receptors in myeloid, lymphoid and tumor cell migration. The knowledge obtained will be integrated into our current understanding of the cellular and molecular basis of pathophysiological events such as acute and chronic inflammation, tumor progression and metastasis. Results generated by this research module have the potential to guide the development of novel therapeutic strategies. The present RM will be integrated as RM3 in a highly synergistic manner (as outlined in the cartoon below) in the existing ProDoc CellMigration, which currently consists of a Training Module (TM), and two research modules, RM1 and RM2. Associating RM1 with RM3, ProDoc Student 13 will investigate the role of CCR2, CX3CR1, Tie2 and their respective ligands in the migration of myeloid subsets into the brain during immunosurveillance and neuroinflammatory disorders such as multiple sclerosis. To this purpose this student will use novel mouse models and mesoscopic and live cell imaging tools and human samples. Research of ProDoc Student 14 will define how synergies between soluble mediators enhance T cell recruitment into tumors, with relevance to natural anti-tumor immune responses and cancer immunotherapy protocols. Work by this student with have natural interactions with RM1 and RM2. Finally, ProDoc Student 15 will study the modulation of chemokine activity in spontaneous and therapy-induced breast cancer metastasis by exploiting recent results and tumor models obtained in the partner laboratories. Research topics addressed within RM3 will be highly related and complementary to experiments proposed in RM1 and RM2 of the running ProDoc CellMigration Program. Embedding three additional PhD students to work in collaborative projects focusing on the role of soluble mediators involved in immune and tumor cell migration will exploit to the fullest the potential for collaborative efforts within the ProDoc consortium. This program provides the framework for an internationally visible training program for highly qualified PhD students in the field of cell migration, excellence of which cannot be achieved at this level in the individual laboratories alone.