Tumours that are deficient in mismatch repair system accumulate numerous mutations throughout the genome in repeated sequences, called microsatellites. Genes that contain microsatellite in their sequence are target genes of microsatellite instability (MSI).The aim of my thesis was to determine the functional consequences of mutations occurring in a newly identified target gene of the MSI oncogenesis : SMAP1 (Small ArfGAP1), which encodes a protein of the ArfGAP (ADP ribosylation factor GTPase Activating Protein) family specific for Arf6, a protein involved in clathrin-mediated endocytosis and actin remodelling. SMAP1 mutations are specific for MSI tumours of various tissue origins and occur in its coding poly (A)10 microsatellite. SMAP1 mutations are especially frequent in MSI colorectal cancers (CRC), in which its mutation frequency decreases with tumour progression suggesting that tumours devoid of SMAP1 mutations are more invasive. Functional experiments allowed us to show that SMAP1 mutations lead to a defect in the fast recycling step of the transferrin receptor trafficking, to increased cell proliferation and to decreased invasiveness by maintaining the adherent junctions. Interestingly, our observations showing that SMAP1 mutations increase the proliferative potential but reduce the invasiveness of MSI CRC-derived cell lines may explain some of the MSI CRCs clinical features, notably their large size and low metastatic potential.
