HGF/SF and MET
in Metastasis

• Home
• Project Overview
  • Project Structure
  • Project Partners
  • Project Management
• Research
  • Hypoxia. MET and cancer invasion
  • WNT, chemokines and MET in cancer invasion
  • Structure of HGF/SF and MET
  • Engineering protein antagonists of MET
  • Small molecules MET antagonists
  • SHP-2 inhibitors
  • Latest Results
• Participants
  • MRC Centre, Cambridge
  • Institute for Cancer Research, Turin
  • Max-Delbrueck Institute, Berlin
  • University of Cambridge
  • Centre for Nuclear Magnetic Resonance, Florence
  • Leibniz Institute for Molecular Pharmacology, Berlin
  • Cambridge Molecular Therapeutics Programme
• Publications
  • 2008
  • 2009
  • 2010
  • 2011
• Job Offers
• Contact
• Intranet

Project Overview

HGF/SF is a motility factor that controls the migration of precursor cells during embryogenesis and epithelial cells in wound repair and tumour invasion. MET is the receptor for HGF/SF. HGF/SF is secreted by cells in the tumour stroma and causes tumour cells expressing the MET receptor to dissociate from neighbours, and leads to the process that degrades the extracellular matrix. As a result, cancer cells migrate away from the primary tumour and can reach the local lymphatic or blood capillaries initiating the later stages of metastasis.

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.

Project Objectives

The objectives of this project are twofold. First, the project aims to address two key mechanisms of MET-dependent tumour invasion, namely:

1. How tumour cells exploit the MET pathway and invade adjacent tissues in order to escape tumour hypoxia (when the tumour is deprived of oxygen).
2. How the MET and other pathways cooperate in metastasis. These studies will contribute to the understanding of the interplay between tumour hypoxia and invasion and between different signalling systems that operate throughout the process of metastasis.

Secodnly, the project aims to develop MET inhibitors for the treatment of metastatic cancer. These include:

1. Protein therapeutics, engineered on the strength of existing crystal structures of fragments of HGF/SF and of new structures of HGF/SF-MET complexes
2. Low molecular weight MET antagonists and,
3. inhibitors of SHP-2, a critical effector of MET signalling.