Background
Increasing evidence shows that tumours are structured according to a hierarchy that includes two main components: (i) at the apex, a (tiny) subset of cancer stem cells (CSCs) that retain unrestricted proliferative ability (self-renewal), and continuously regenerate or add to the tumour; (ii) at the base, a large subset of cells that, unlike CSCs, retain restricted proliferative ability, and undergo aberrant differentiation. This hierarchical model implies that CSCs must be eradicated in order to cure the tumour. The task is challenging, as CSCs are often resistant to therapies (including targeted drugs) otherwise effective against the remaining cancer cells, and can be responsible for cancer relapse in apparently cured patients. In order to envisage more effective therapeutical strategies, we aim to investigate the genetic and molecular mechanisms that account for CSC sensitivity or resistance to conventional radio- and chemo-therapy, or innovative oncogene-targeted therapies.
Achievements
A mechanism of CSC resistance to be first considered is activation of MET, the oncogene encoding the tyrosine kinase receptor for HGF, which controls invasive growth in either physiological (embryo development and tissue regeneration) or pathological (cancer) conditions. We recently reported that, in irradiated tumour cells, MET is upregulated by DNA damage detection, and activation of the ATM-NF-?B signalling pathway. We showed that, once upregulated, MET fosters survival and "adaptive resistance" of irradiated cells. Vice versa, abrogation of MET expression, or inhibition of its kinase activity by specific drugs, irreversibly block cell proliferation, and promote apoptosis. In preclinical models, administration of MET inhibitors increases the efficacy of radiotherapy. Thus, we have found that MET mediates a molecular mechanism of radioresistance, and provided a rationale to combine radiotherapy with drugs that inhibit MET.
Goals
In CSCs derived from colorectal cancer, glioblastoma, and other tumours, we are studying whether the MET oncogene mediates resistance to irradiation and other DNA-damaging agents. Moreover, as MET drives invasive growth, we are studying whether it controls the CSC ability to self-renewal and disseminate. We are then testing whether specific small-molecule kinase inhibitors and monoclonal antibodies targeting MET, alone or combined with radio- and chemo-therapy, can be exploited to eradicate CSCs.
Selected publications
F. De Bacco, P. Luraghi, E. Medico, G. Reato, F. Girolami, T. Perera, P. Gabriele, P.M. Comoglio, and C. Boccaccio. Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer. J. Natl. Cancer Inst. (2011) 103:645-661.
C. Boccaccio and P.M. Comoglio. Genetic link between cancer and thrombosis. The Journal of Clinical Oncology (2009) 27:4827-4833.
C. Boccaccio and P.M. Comoglio. Invasive growth: a MET-driven genetic program for cancer and stem cells. Nat. Rev. Cancer (2006) 6:637-645.
C. Boccaccio, G. Sabatino, E. Medico, F. Girolami, A. Follenzi, G. Reato, A. Sottile, L. Naldini, and P.M. Comoglio. The MET oncogene drives a genetic program linking cancer to hemostasis. Nature (2005) 434: 396-400
