Molecular mechanisms of cancer and ageing

The cancer stem cell hypothesis provides an appealing perspective through which we can examine cancerogenesis and tumour progression, and suggests a rationale for therapeutic interventions. A major focus of our group is to generate appropriate mouse model systems of human cancer for the characterization of cancer stem cell properties and their molecular determinants. We are also investigating the effects of metabolism and checkpoint activation in SCs on tissue homeostasis and ageing.

Laboratory Achievements

Our lab has made, in the past, original and seminal contributions to the understanding of the molecular basis of:

• i) leukemias (i.e. identification and functional characterization of the PML-RAR and mutated-NPM oncogenes; definition of the molecular basis of targeted treatment with retinoic acid and HDAC inhibitors);
• ii) ageing in mammals (i.e. identification and functional characterization of the Shc family of signaling proteins; characterization of the red-ox properties and effects on life span of the p66shc splice variant).

More recently, we have contributed to the preliminary understanding of the self-renewal properties of cancer stem cells (in leukemias and mammary tumors), showing that they possess: i) increased replicative potential, due to the up-regulation of the cell-cycle inhibitor p21 and the prevention of excess DNA-damage accumulation; ii) increased frequency of symmetric divisions, due to p53 inactivation.

Laboratory Research Projects

We are currently continuing to pursue our two main lines of research, focusing on:

1. The characterization of the CSC-specific properties of self renewal and differentiation, and their underlying molecular mechanisms, using mouse models of human leukemias and mammary cancer. In particular, we are exploring:
   • the role of quiescent and proliferating CSCs in tumor growth,
   • mechanisms of tumor progression from pre-tumoral SCs,
   • molecular determinants of environmental cancer risk
   
   
2. The characterization of the physiological significance of the p66Shc signaling pathway, with particular emphasis on metabolism, apoptosis and the adipose tissue.