THE ENDOCYTIC AND CYTOSKELETAL MATRIX IN THE PLASTICITY OF TUMOR CELL INVASION AND MIGRATION

Tumour cells can adopt different modes of cell motility. The ability to switch between diverse modes of migration enables tumours to adapt to micro-environmental conditions and to metastasize. The critical pathways and cellular processes underlying the plasticity of tumour cell motility have only begun to be identified. Endocytosis, originally thought of as a device to internalize nutrients and membrane-bound molecules, is emerging as a connectivity infrastructure (which we call "the Endocytic Matrix") of different cellular networks necessary for the execution of various cellular programs. A primary role of the Endocytic Matrix is the delivery of space- and time-resolved signals to the cell, and it is thus essential for the execution of polarized functions during cell migration. The molecular mechanisms it uses are, however, ill defined and likely to involve, in addition to extranuclear pathways, also transcriptional programs. In this respect, we have acquired evidence that components of the Endocytic Matrix require de novo gene expression to promote the transition in the mode of tumour cell motility. We propose to identify critical components of the Endocytic Matrix that by controlling the cellular location of actin remodellers promote the plasticity of tumour cell migration. We will also test whether, in addition to the immediate epigenetic/signalling-based control of migration, the Endocytic Matrix regulates transcriptional programs required for the acquisition or maintenance of diverse modes of motility. Finally, in view of the key role of microRNAs (miRNAs) in cancer, we will use miRNA profiling, together with endocytic cell migration and invasion assays in human cancer cells to test whether miRNAs mediate the relationship between endocytosis and motility programs.