Researchers led by Spanish National Cancer Research Centre's (CNIO) Marcos Malumbres have decoded a new mechanism that regulates cell division and found that the key molecule involved in the mechanism, known as Greatwall − or Mastl−, can be targeted for development of new oncology treatments, a new study published in the Proceedings of the National Academy of Sciences.
GREATWALL: A KEY PLAYER OF THE CELL DIVISION PUZZLE
The control of cell division or mitosis depends on many proteins, amongst them, Aurora and Polo. Currently, many pharmaceutical companies have shown interest in these molecules, for which inhibitors have already beendeveloped, some of which are currently undergoing clinical trials in oncology.
Greatwall, the protein Malumbres's group has focused their work on, is also a protein that regulates cell division. Until now, almost all of the studies on this protein were carried out on the Drosophila melanogaster fly or on other invertebrate bodies. CNIO's Cell Division & Cancer Group, in collaboration with researchers from the National Centre for Scientific Research (CNRS) in Montpellier, France, has now generated the first genetic model of this protein in mammals, using the mouse as a model.
Thanks to this mouse model, the authors of the work have been able to see that cells lacking Greatwall are not capable of adequately dividing themselves: by eliminating Greatwall, cellular DNA does not form the right structure at the moment of cell division, the cell collapses and this prevents them from continuing to divide.
A NEW TARGET FOR CANCER THERAPY
As Mónica Álvarez Fernández, one of the group's researchers and the first author of the article, says: "the next step now is to explore the potential therapeutic applications of this discovery".
One of the therapeutic advantages Greatwall offers, and one that differentiates it from other mitotic proteins, is that it acts by blocking the function of the PP2A phosphatase, a tumour suppressor frequently altered in human cancer. This implies that the inhibition of Greatwall could, at the same time, slow down cell division and reactivate tumour suppressor PP2A, a protein capable of inhibiting many of the oncogenic molecular pathways involved in cancer development.
The key now is to find out which tumours would benefit from using this strategy, as well as to develop compounds capable of inhibiting this protein. With regard to both of these aspects, CNIO's research group is already actively working with other groups and clinical units.
"Therapeutics development is currently in need of novel targets that attack tumours in a different way", says Malumbres, "and Greatwall offers new strategies amongst which can be found reactivating a very important tumour suppressor, something for which there are no direct therapies at the moment".