Research topics
Unleashing the intrinsic tumor suppressive properties of tyrosine kinase oncogenes to kill cancer cells.

Background
Intrinsic tumor suppression is an innate and self defeating program that evolution has associated to oncogenes to balance the threatening one, i.e. the triggering of malignancy. Oncogenic tyrosine kinases (TKs) might harbor intrinsic tumor suppressive functions. They sit at the apex of multiple downstream signaling pathways that exert various biological effects depending upon cell type and context. While some of these pathways are mitogenic and pro-survival, others might restrain the oncogenic potential by promoting, for example, apoptosis and senescence. Obviously, the latter programs do not confer a selective advantage to neoplastic cells and thus they are hidden in cancer cells. However, intrinsic tumor suppression of TKs might be unleashed to kill cancer cells.

Achievements
We had demonstrated that activation of the MET TK results in the commitment to death of ovarian cancer cells. Using a phosphoproteome and a transcriptome approaches we have now identified transducers and effectors of the pro death activity of this TK. Among the transcriptional targets we have found proteins which play specific roles in ovarian cancer cells, killing the latter cells and sparing other cells. We have also identified a heat shock protein (HSP) which protects cells from the intrinsic apoptotic effect of MET TK over activation. This HSP can be targeted to kill cells where MET is activated.

Goals
The goal of this Laboratory is to exploit the mechanism of the death signalling elicited by the MET TK in ovarian cancer cells as it will be introductory to the conversion of survival signals triggered by TK oncogenes into death signals. Therefore we will study the effect of MET activation in other cell lines and the possible similar outcome of the over-activation, by either over-expression or mutation, of other TKs, such as EGFR and HERII. The identified molecules will be validated using an array of assays in vitro and in vivo.

Internal collaborations
Laboratory of Molecular Biology and of Molecular Pharmacology that are similarly interested in the signal transduction evoked by ligands of TK receptors; Surgery and Gynecology clinical units with the aim of validating the transferability to patient treatment of the finding from the laboratory.