Identification of metastasis suppressors

The cure of most cancers will ultimately depend on our capacity to treat the metastatic patient, displaying disseminated secondary tumors that typically does not respond to chemotherapy. We aim to gain a better understanding of the molecular drivers of metastasis in order to develop sorely needed prognostic markers of metastatic relapse, predictive markers of treatment response, and ideally anti-metastasis therapeutics. To meet these formidable challenges, we are investigating metastasis-regulating genes, whose clinical relevance is validated in large cohorts of patients. In particular, we pioneered the notion that p63, a p53-related transcription factor, acts as bona fide "metastasis suppressor" gene in epithelial tumors (Adorno et al., Cell 2009). We also showed that p63 activity is opposed by mutant-p53, providing a mechanism for the high-frequency of mutant-p53 expression in aggressive human cancers, and mutant-p53 association to poor outcome. We further expanded on metastasis-suppressor genes by the identification of the anti-metastatic functions of two p63 target genes, Dicer and Sharp1 (Martello et al., Cell 2010; Montagner et al., Nature 2012).

We are now focusing on the possibility to reactivate metastasis suppressor genes as a mean to sustain the dormancy of microscopic lesions.

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