Reproductive Cancer Cell Biology

Research Leaders: Dr Darryl Russell and Dr Carmela Ricciardelli

The Reproductive Cancer Cell Biology group studies the interaction between cancer cells and their microenvironment that promotes the progression of reproductive organ cancers to invasive and metastatic disease.

About 1/3rd of breast and prostate cancer patients will develop metastatic disease which available therapies cannot cure. Advances in early detection of malignancies have done little to improve the proportion of patients who face early relapse and mortality due to the disease.

This group is investigating the molecular mechanisms that enable these metastatic cancer cells to detach from the primary tumour mass and migrate into blood or lymphatic vessels that give them passage to new sites where metastases establish. To do this cancers acquire the capacity to remodel their surrounding extracellular matrix by making key protease enzymes.

The group has identified specific members of a protease family known as the ADAMTS family, which is associated with poor prognosis for breast and prostate cancers respectively. We are using mouse models of cancer metastasis as well as cell culture systems with engineered over-expression or knock-down of specific genes with specific gene mutations to investigate the influence of proteases on metastatic cellular behaviour.

These exciting results show that members of the ADAMTS family of protease enzymes are produced by aggressive cancer cell types in human disease and in our mouse models. These promote remodelling of the extracellular matrix that normally surrounds cancers, changing the interactions between tumour cells and their neighbouring nonmalignant stromal tissue to enhance tumour growth and metastatic spread. This work is revealing potential biomarkers to identify the patients who are at risk of metastatic relapse as well as promising therapeutic targets to block the metastatic process.

Research Priorities:

• Characterising mechanisms by which ADAMTS proteases promote tumour grade and metastatic progression in
  mouse models
• Determining the association of protease expression with tumour grade and prognosis in human patients
• Identifying protease substrates in tumour associated extracellular matrix
• Understand the consequences of protease-substrate interaction for metastatic behaviour of human cancer cell lines in a range of culture systems
• Identifying effective inhibitors of ADAMTS catalytic activity or their products as potential anti-metastatic therapeutics