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Flavio Maina has completed his PhD at the University of Turin (Italy) and postdoctoral studies at EMBL (Germany). He is group leader at the IBDM since 2000. He was recruited at the CNRS as CR1 in 2000, got the HDR in 2005, then promoted DR2 in 2010 and DR1 in 2015. He has published more than 50 papers in reputed journals. His team studies how qualitative and/or quantitative receptor tyrosine kinase (RTK) signaling changes lead to diversified cell behaviors. By applying integrative approaches, the team explores vulnerability versus resilience of cells to signaling fluctuations, and how cell plasticity intercalates such signaling changes. Most of team projects are based on interdisciplinary approaches. Strong scientific team competences include those on: RTK signaling, cell signaling mechanisms, mouse genetics and development, gene targeting, stem cell biology, and liver cancer. Research is performed by intercalating phenotypic and mechanistic studies in cultured cells and in vivo.
Aberrant receptor tyrosine kinase (RTK) signaling is essential during liver cancer evolution and resistance to therapies. Using mouse genetics, we recently demonstrated that a subtle increase of wild-type RTK levels leads to cancer in sensitive tissues, illustrating how the shift towards cancerogenesis can stem from a slight perturbation of signaling dosage. In particular, when the Met RTK is slightly enhanced in liver, mice (namely Alb-R26Met) spontaneously develop hepatocellular carcinoma (HCC), which belong to the so called “proliferative progenitors” subclass (Fan et al. Hepatology 2017 Nov;66(5):1644-1661).
To uncover new genes that cooperate with RTKs during tumor initiation, we combined the clinically-relevant Alb-R26Met mice with the Sleeping Beauty (SB) transposon (T2/onc) mutagenesis system. Whereas neither Alb-R26Met nor T2/onc-Alb-R26SB/+ mice developed tumors at 30 weeks of age, T2/onc-Alb-R26SB/Met mice (with enhanced Met in liver in addition to active SB-driven mutagenesis) developed multiple liver tumors, each carrying distinct genomic insertions. Analysis of 251 independent tumors led to the identification of 285 putative cancer-related genes: some of them correspond to known proto-oncogenes or tumor suppressors, thus validating the overall strategy we employed for cancer gene discovery; other genes have not previously linked to cancer. Integrative analysis with human data revealed that a large proportion of identified genes are also altered in HCC patients. Moreover, we compared our screen outcomes with those performed in other tumor-sensitizing contexts and found 71 genes that emerged specifically in our RTK-sensitized background. In vivo assays established the functional relevance of several new putative tumor suppressors.
Overall, our screen strategy identifies new functional mechanisms destabilizing liver homeostasis and illustrates how a subtle increase in wild-type RTK levels provides a permissive context for several types of cooperative mechanisms leading to liver tumor initiation.