Objective
Objectives:
The objective of this project is to elucidate the molecular mechanisms by which the activation of the c-MET oncogene leads to tumor metastasis. This goal will be achieved by: (A) The development of mouse models for Met-mediated metastasis and (B) The identification of the cellular processes controlled by Met whose deregulation leads to metastasization.
Brief description:
It has been established that failure of a successful treatment in cancer patients is due to the metastatic activity of the tumor. A group of co-ordinated cellular processes is responsible for metastasization. Genetic lesions result in growth deregulation and lead to uncontrolled proliferation. However, unrestrained growth does not, by itself, result in invasion and metastasis. In addition to loss of growth control, an unbalanced regulation of motility and invasion is required for the metastatic phenotype. The Hepatocyte Growth Factor (HGF) receptor family includes tyrosine kinases encoded by three protooncogenes: MET, SEA and RON. The members of this gene family share unique functional features: in physiological conditions -besides growth- they mediate cell dissociation ("scattering") and morphogenesis. In their oncogenic versions they trigger cell transformation, invasiveness and metastasis. The recent identification of germline and somatic mutations of the c-MET oncogene in patients affected by papillary renal carcinomas establishes a direct genetic connection between MET activation and human cancer. Furthermore the c-MET oncogene is overexpressed in a significant percentage of primary cancers and is amplified in metastasis, suggesting a direct involvement in progression toward malignancy. This conclusion is supported by the observation that cells transfected with an activated version of the c-MET gene acquire invasive and metastatic properties, both in vitro and in nude mice. Within the time frame of this project the mechanisms by which the activation of the c-MET oncogene leads to the invasive-metastatic phenotype will be studied. Mouse lines, to be used as "conditional metastasis models", will be constructed by preparing transgenic mice in which the expression of the HGF ligand will be confined to specific tissues. These models will then be used to study the metastatic potential of a number of cellular systems in which c-Met controls specific signalling pathways. Identification of the c-Met driven cellular landmarks leading to metastasis should allow the design of signalling inhibitors able to interfere with the metastatic processes driven by this oncogene.
Keywords:
Cancer, Metastasis, Invasion, Oncogene, HGF/SF, c-MET
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
10126 Torino
Italy
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