HGF/SF and MET in metastasis
Coordinator: Ermanno GHERARDI
Project Number: 201640
EC contribution: € 2,927,008.00
Project website: http://www2.mrc-lmb.cam.ac.uk/sfmet/index.html
The growth and motility factor HGF/SF and its receptor MET define a paracrine signalling system which controls the migration of several cell lineages in embryogenesis and tissue repair. In a large number of human tumours, cancer cells hijack HGF/SF and MET signalling in order to invade adjacent tissue and initiate metastasis. The evidence for this is strong, broad and consistent and highlights HGF/SF and MET as key effectors of tumour invasion and primary targets for therapy. This proposal has two objectives. The first is to understand the mechanism by which HGF/SF and MET cause tumour invasion and, specifically:
- how local hypoxia induces MET over-expression in tumour cells and how the MET
- WNT and the MET
- chemokine pathways cooperate in metastasis.
The second aim is to develop MET therapeutics. These will include:
- a protein antagonist built from a fragment of the ligand known as NK1,
- low molecular weight MET antagonists and,
- inhibitors of SHP-2, a critical effector of MET signalling.
NK1 will be engineered as a receptor antagonist on the strength of available crystal structures. Low molecular weight MET antagonists and SHP-2 inhibitors will be developed on the strength of:
- the availability of recombinant forms of the target proteins,
- suitable screening methodologies and,
- the results of initial screens that have provided robust proof of principle for both approaches.
The proposal thus builds on strong progress in participating laboratories on the structure and function of HGF/SF and MET and fulfils the three key criteria described in the call for proposal ‘Understanding and fighting metastasis’, namely:
- it addresses a key mechanism of dissemination of human tumours,
- contributes to understanding the interplay between the tumour microenvironment (the source of HGF/SF) and tumour cells (the cells that express the MET receptor) and,
- has considerable prospects of delivering novel therapeutics for metastatic cancer.