Although cancer stem cells (CSC) have received much attention in the recent scientific literature, they are still defined by their self-renewal capability, a feature that on its own does not encompass other essential characteristics of these cells, e.g. their capacity to detach and migrate away from the primary site and invade distal organs. This operational definition of the migrating cancer stem cell (MCSC) is integral to another feature of neoplastic diseases, namely tumour heterogeneity. CSCs give rise to differentiated cells by asymmetric division thus providing a reservoir of multi-potent descendants together with proliferating but progressively differentiating cells. Recent experimental evidences point out that cancer stem cells are key factors not only in local invasion and distant metastasis but also in the development of drug resistance, thus representing the target for novel strategies towards tailor-made cancer therapies.
The increasing knowledge of the structure and regulation of the mouse and human genomes together with the awareness that migrating cancer stem cell could be the ultimate target for effective therapies offer unprecedented research opportunities. This proposal is designed to seize these opportunities and is focused on understanding the function, regulation and evolution of MCSCs in a multi-cellular organism. To this end we plan to identify and isolate breast and colon MCSCs by taking advantage of unique reagents, animal models, and technical approaches, and translate the results on large collect- ions of human cancers, disseminating cancer cells, and metastases. The ultimate goal is to describe and functionally analyse the MCSCs and their micro-environment (the MCSC niche) and define a 'MCSC signature', instrumental for the development of future tailor-made therapeutic approaches.
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