The team have discovered link between two common features of cancer: cell invasion and a phenomenon called centrosome amplification.
Invasive MCF10A acini (cell clumps) after 4 days'
growth in 3D culture. F-actin in red, fibronectin in
green, DNA in blue. An invasive protrusion is visible
(red extension). Image by Dr S. Godinho.
In human cancer, it is usual for cancer cells to explore and invade the surrounding tissue more and more as the condition progresses, until some cells break away from the original tumour and move to other parts of the body (called metastasis).
Here at BCI, much of our research is dedicated to understanding how and why cells become more invasive in normal, precancerous and cancerous tissues. Improving our understanding of the processes that lead to metastasis is vital in designing better treatments and preventing disease progression.
Centrosomes are organising “stations” that form in dividing cells. They help construct and manage protein "cable" structures, called microtubules (collectively called the spindle), that pull apart pairs of chromosomes during mitosis (cell division).
Their job is to ensure that the cell's replicated DNA is separated evenly into the two daughter cells, to avoid the build-up of genetic abnormalities. Normally there are two centrosomes per cell - each organising a "terminal" for the chromosomes to be pulled towards in cell division.
The Godinho lab focuses on breast cancer, investigating how tumourigenesis is affected in a variety of modelling systems, including 2D and 3D cell culture. These systems allow researchers to look at the behaviour of cells in different environments when their characteristics are changed.
In cancer, the DNA content of cells can become increasingly disorganised as mutations build up and the cell loses the ability to fix problems during cell division. This can include centrosome amplification - cells end up with more than two centrosomes at a time. Usually this leads to cell death, or the creation of daughter cells that have too much or too little DNA.
The consequences of extra centrosomes
Susana's group developed a technique to temporarily increase centrosome number in a type of breast cell called MCF10A. They used 3D culture methods to grow them and study the cells' behaviour in the lab. They found that manipulating the number of centrosomes could promote invasive cell behaviour and discovered two causes of the invasive properties:
- speeding up the construction of the microtubule spindle in the cell ("microtubule nucleation") from the multiple centrosomes
- activation of a protein called Rac1, which is important for cell invasion and often "hyper-activated" in tumours.
Studies of human tumour samples have shown that centrosome amplification correlates with advanced disease (samples of high grade tumours often contain cells with extra centrosomes), but the reasons for the association are still unclear; is centrosome amplification a cause, a consequence, or merely a coincidence in the progression of cancer? The findings in this new study suggest that it might be at least partly a cause - the activation of the protein Rac1 and promotion of invasion could partly explain why we tend to see extra centrosomes in high grade tumours and poor patient prognosis.
Can we target the centrosomes?
There are clearly more questions to explore about the roles of extra centrosomes in cancer cell behaviour. We now know that part of the mechanism that causes invasion includes the activation of the protein Rac1, but that is unlikely to be the whole story since the centrosome play multiple roles in cells. Understanding how centrosome amplification induces invasion and contributes to tumour progression is essential for our understanding of the role of extra centrosomes in cancer.
Dr Godinho's previous work described a mechanism that allows cancer cells with extra centrosomes divide efficiently and survive ("centrosome clustering"), avoiding the usual deadly fate of cells that fail to regulate their centrosome numbers. She said:
Targeting this mechanism, namely centrosome clustering, can specifically kill cancer cells carrying extra centrosomes.
Finding therapies that are specific in this way, killing cancer cells while leaving normal cells unharmed, is the goal of many current cancer research projects. Widely-used chemotherapies often target more general characteristics like cells dividing or proteins/pathways common to many cell types; finding cancer-specific features to target with new drugs can lead to treatments that are far more tolerable for patients, and effective at stopping cancer growth.
These initial findings suggested that targeting centrosome clustering could be a therapeutic strategy and, consequently, small molecule drugs were recently developed. This recent paper showing that centrosome amplification can directly induce invasion also supports further research into killing cells with extra centrosomes and that this might indeed be effective for the patients in future.
Oncogene-like induction of cellular invasion from centrosome amplification Susana A.Godinho, Remigio Picone, Mithila Burute, Regina Dagher, Ying Su, Cheuk T. Leung, Kornelia Polyak, Joan S. Brugge, Manuel Théry, David Pellman. Nature (2014). 508 (7495), Advanced Online Publication
You can read more about centrosome-related projects in Meet a PhD Student: Alex Pool