Vessel-guided collective cancer invasion in vivo: molecular mechanisms and fate

• Applicant: Professor Dr. Peter Friedl
• Subject Area: Pathology
• Term: from 2006 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 22053007

Cancer invasion and metastasis are the result of promigratory activity in tumor cells which is in part induced and directed by structural and molecular signals provided by the tumor microenvironment. The tumor vasculature represents both, a structural and molecular scaffold for tumor cell invasion. Structurally, vessels provide aligned fibrillar and basemement membrane ECM structures together with elongated endothelial cell bodies for direct engagement of tumor cells. The molecular proinvasive elements are ECM domains engaging integrins, released MMPs and other proteases for receptor processing, and cell surface molecules supporting heterophilic cellular interactions, including ephrin-B2/EphB4, N-/VE-cadherin, or NCAM. We will investigate how tumor vessels and neovessels contribute to tumor cell invasion by using dynamics imaging in 3D ECM based confrontation assays as well as intravital multiphoton microscopy of GFP/RFP expressing tumor cells in the nestin/GFP nude mouse. Using time-resolved topographic reconstruction and interference with soluble antagonists or RNAi, target functions will be ECM remodeling for guided migration and the provision of basement membrane and other aligned ECM structures. A key focus will aim at direct heterologous tumor cell-EC interactions via Ephrin/EphB pathways mediating dynamic cell-cell contacts. Concepts will be established using ECM in vitro confrontation assays and then validated by intravital multiphoton microscopy. These studies will provide new concepts on molecular switches of tumor invasion beyond integrin-mediated cell-matrix interactions.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1190: The Tumour-Vessel Interface