The project explores the exciting possibility that cells which escape into the blood stream exhibit a phenotype reminiscent of certain developmental phases. Confirmation of this will provide new treatment avenues and new opportunities for diagnosis.
Tumour cells from cancer in the breast are able to spread around the body, lodge in different tissues (metastasise) and, despite hormonal or chemotherapy, lie dormant until clinically detectable as a recurrence. The survival of these cells in new environments is paramount to breast cancer recurrence and mortality.
An exceptional window into breast cancer recurrence are the circulating tumour cells (CTC) and disseminated tumour cells (DTC) that can be isolated from the blood stream and bone marrow, respectively, of patients with breast cancer.
During embryonal development, in order create new tissues, epithelial cells undergo ‘epithelial-to-mesenchymal transition' (EMT) to acquire migratory and other (non-epithelial) properties. Once they have migrated from the site of origin, the reverse transition (MET) allows these cells to become a new tissue. We use the term epithelial-mesenchymal plasticity (EMP) to describe the variety of behaviours and shapes (‘states') that cancer cells can adopt along the EMT-MET axis.
EMP is now also recognized to occur in cancer, especially in the molecular and functional overlap between EMP and breast cancer stem cells, a population of cells with high capacity to form tumours and to metastasise. Our research is based on the hypothesis that EMP is a significant contributor to metastasis, through conferring tumour-promoting abilities on CTC and DTC, such as survival in new environments and resistance to therapies.
The EMP status of CTC and DTC therefore has potential to be both a predictor of recurrence and a monitor of response to cancer therapy.
Our goal is to extend basic EMP research into the clinic. As a first step, the ethics committee has approved our application to, with the patients' informed consent, collect samples of bone marrow and blood at the time of hip replacement surgery due to breast cancer metastasis to bone.
We have completed the first accrual and have optimised the methods for isolating CTC and DTC using magnetic beads coated with molecules that capture cells through their surface proteins. The determination of the EMP status of the CTC and DTC is ongoing. Our other studies are on human breast cancer cells grown in mouse mammary fat pad, which allows us to monitor the blood and bone marrow for CTC and DTC, respectively, in a more reproducible and controlled way and to test hypotheses experimentally. We have used two different human breast cancer cell lines and confirmed preliminary indications of EMT at
the edges of the mammary fat pad tumours which may be where CTC and DTC arise from.
We are manipulating these cell lines so they either cannot undergo EMT (i.e. they remain stationary and ‘epithelial') or are forced into a migratory ‘mesenchymal' state, so that they cannot undergo MET. Manipulated cells will be reassessed in mouse to see what effects the manipulations have on the formation of CTC, DTC and metastases.
A/Prof Erik Thompson, Prof Peter Choong, Dr Prue Hill, A/Prof Michael Henderson, Prof Klaus Pantel
Cancer Council Research Grant
University of Melbourne
$94,700 in 2009, $95,700 in 2010