Objectives

The specific objectives of the MetaFight project are:

1) To break down and identify the harmful aspects of the Core Invasive Machinery signalling in metastasis outgrowth by a "Systems Biology Analysis" of the early events generated by this platform in disseminating tumour Cells.

This includes analysing how changes in molecular architecture in metastatic cells occur, how this is perceived and connected into intracellular signals and how these signals change the migratory and invasive cell phenotype. Dissection of signalling will be carried out in highly metastatic cells where signalling events will be quantified and characterised in vitro in a standardised and comparable manner. Particular emphasis will be put on in vivo analysis of mouse models of spontaneous tumour and metastasis formation with genetic manipulations leading to over-expression or knocking-down of specific pathways involved in the Core Invasive Machinery .

2) To evaluate the fate of single metastatic cells within the mouse, by taking advantages of imaging non invasive strategies.

The MetaFight Consortium will heavily exploit fluorescence imaging system, bioluminescence, enhanced tomography and ultrasound scan that have been recently developed for use in small animals. Imaging studies for metastasis will include single-cell imaging studies that will shed new light on the biology of metastasis and the interactions of metastatic cells with their microenvironment early in the process of metastasis (Deroose et al. , 2007; Soon et al. , 2007). The option to detect metastatic cell clusters and gross metastases within the whole animal, using imaging, will also facilitate the inclusion of metastasis endpoints in the pre-clinical development of new drugs.

3) To uncover candidate targets that will be exploited: (i) to enhance the understanding of signalling and (ii) to develop new treatment strategies in a joint translational research activity.

Different screening techniques will be applied such as an RNAi-based systematic screen for kinases involved in controlling the migratory machinery, and a systematic proteomics-based approach to identify molecular mechanisms involved in cell motility and invasion. Quantisation of changes in protein expression and phosphorylation in metastatic cells will be achieved using the novel techniques of stable-isotope labelling by amino acids in cell culture (SILAC) or in mice (SILAM) combined with mass-spectrometric and bioinformatics technologies. Also, small molecules, peptides and proteins will be screened for their potential to alter migration and invasion and the related signalling pathways. This will be followed by development of gene targeted treatments using conventional drug development and RNAi technology.

4) To develop new strategies to inhibit detrimental and to promote beneficial signals for blocking metastasis outgrowth exploiting the knowledge on the key Core Invasive Machinery .

This strategy includes translational research on existing molecules, proof of principle studies with molecules already developed by the partners of the consortium and the development of new candidate molecules identified during the course of the integrated project. Candidate targets (genes or proteins) will be tested for their effects on invasion and metastasis in a series of model platforms of highly metastatic cancer cells via engineered orthotopic xenografts. Also, human cancer tissue banks will be screened for the expression of the best candidate targets.

5) To increase the knowledge of experts and the lay population regarding metastasis by collaborating with European Societies and national programs.