Research topics
Molecular mechanisms regulating cell adhesion and cell division.

Background
The processes of cell division and cell migration are both outstanding issues in cancer research being deregulated in the majority of tumours. Chromosomal abnormalities arise mainly from defects in chromosomes segregation during cell division and they have long been recognized as distinguish feature of cancer cells. Moreover, tumours, in order to metastasize and grow, must invade the surrounding tissues and this is achieved through the activation of signalling cascades that control cell adhesion and migration. The identification of the complex molecular wiring that connects these pathways would provide novel targets for cancer terapy.

Achievements
We recently identified a novel function for Rab5, a critical GTPase controlling membrane trafficking in mitosis. We found that endocytic trafficking occurs at mitosis as we detected a pool of Rab5-positive vesicles moving on spindle microtubules. RNAi-mediated silencing of Rab5 caused defects in chromosome congression and an extensive prometaphase delay. Analysis of Rab5-silenced cells revealed a decrease in the stability of kinetochore-fibers and a severe reduction in the localization of the centromere protein CENP-F at kinetochores. CENP-F is required for chromosome congression and stable microtubule capture at kinetochores.. Thus we propose that Rab5 facilitates chromosome congression by promoting proper localization of the outer kinetochore component CENP-F.
Our second line of research, points at elucidating the role of Rab5 in the establishment of cell to cell and cell to matrix adhesion. We are currently characterizing RN-tre, a Rab5-negative regulator, as a novel component of cell adhesive sites. We demonstrated that it co-localizes with adhesive markers and that it is required for efficient cell adhesion. We noticed that mouse embryo fibroblasts (MEF) derived from the RN-tre knock out mice appear to have upregulation of active b1 integrin at the cell surface.

Goals
We aim at characterizing the function of endocytic proteins in cell adhesion and during mitosis. To this end, based on our results, we plan to: (i) identify the molecules that are transported by Rab5 during mitosis (ii) to determine the role of Rab5-mediated trafficking in kinetochores assembly and/or stability, (ii) depict the role of endocytic proteins in a) integrin traffic, b) integrin downstream signaling (c) focal adhesions turn over. Furthermore, we will investigate the contribution of tissues expressing high levels of active integrins in tumor vascularization and in tumor cells dissemination and homing by investigating these processes in the RN-tre KO mice.

Internal collaborations
Laboratory of Cell Biology: identification of novel signaling pathways associated with receptor complexes; Laboratory of Cell Adhesion Dynamics: role of endocytic proteins in cell adhesion.

This laboratory is part of the AIRC START UP program.