Background
In some tumors one single hyperactive oncogene is both necessary and sufficient to maintain the transformed phenotype, despite the progressive accumulation of many other genetic and epigenetic insults (‘oncogene addiction’). In therapeutic terms, pharmacological inactivation of the addictive oncoprotein leads to cell-cycle arrest and/or apoptosis, with consequent regression of the tumor mass. The identification of the signaling circuits that govern drug sensitivity in oncogene-addicted tumors is of primary importance to understand the molecular mechanisms that predict responsiveness to targeted therapies and to provide preclinical hints for rational patient selection.
Achievements
In the past years we have identified unconventional signals triggered by the Met tyrosine kinase. Based on experimental data, we have proposed a model whereby Met association with ‘private’ signaling partners is required to fine-tune ‘public’ signaling outputs and to confer signal specificity to Met-triggered transduction pathways. Along this line, we have recently found that Met blockade in MET-addicted cancer cells impacts on a limited subset of Met downstream signals: only some of them are neutralized, whereas many others remain unspoiled. This points to the presence of ‘dominant’ and ‘recessive’ nodes among the numerous oncogenic networks regulated by tyrosine kinase receptors and active in cancer. Finally, we have introduced the concept of ‘oncogene expedience’, as opposed to ‘oncogene addiction’; this notion explains the role of Met as an adjuvant pro-metastatic gene in those tumors in which Met does not act as the genetic determinant of the transformed phenotype, but as a ‘physiological’ expedient to exacerbate the malignant properties of already transformed cells.
Goals
Our objective is to unravel and functionally validate the signaling pathways that selectively mediate drug sensitivity and therapeutic responsiveness in known and candidate oncogene-addicted tumors, as a predictive basis for the rational identification of novel tumor targets. To this aim, we will use different technological platforms (phosphoproteomics, gene expression profiling, DNA sequencing, gene copy number analysis) and various experimental settings (cell lines, ‘xenopatients’, i.e. xenografts of patient-derived material, and genetically modified animal models). Our experimental pipeline involves the use of ‘integromics’ for discovery and hypothesis validation, followed by preclinical validation in animal models. This goes along with the establishment and the implementation of a quality-checked bio-bank of patient-derived material for molecular analyses. Long-term storage of samples under vital conditions is a prerequisite for prospective animal implantation and a unique added value of our endeavor.
Internal collaborations
Laboratory of Cancer Stem Cell Biology: mammary stem cells; Laboratory of Molecular Biology: semaphorin and plexin expression in surgical samples; Laboratory of Cellular Biology: oncogene addiction; Laboratory of Molecular Genetics: xenopatiens; Laboratory of Oncogenomics: gene expression; Division of Surgical Oncology: surgical samples.
