Research and Advanced Education
Oncology and Cancer - Cancer Biology Unit | Prof. João Taborda Barata
photo: IMM website
João Taborda Barata
Director, Cancer Biology Unit
Cancer Biology Unit: rationale
At the Dana-Farber Cancer Institute, in Boston, where I did my PhD over ten years ago, the lifts accessing the various floors of laboratories and to the floors for the care and treatment of patients often had pamphlets notifying people about therapy sessions through music. The intention was not to mislead people suffering from cancer with the false mirage that cure comes about quietly glued to the notes of a harmonious concert for violin and orchestra. The care of patients and their families is constant and caring, but it cannot avoid the suffering that the disease and treatment itself entail. Cure, when it happens, is neither swift nor smooth. Music is only a palliative, a counterpoint to the necessary aggressiveness of current therapies, which cannot eliminate tumour cells without affecting, to a greater or lesser extent, normal cells.
This is why that, not only at that Institute, but also at the Institute of Molecular Medicine (IMM) and at many other centres all over the world, various laboratories focus on scientific research, whether basic or clinical, in the field of cancer. This is due to the fact that it is through research that we will find ways to truly eradicate the disease or, at worst, minimize the need for therapies that affect the quality of life in the short and long term. This is also the reason why the Cancer Biology Unit of the IMM was set up in April 2006. Like so many others, we seek to understand the reasons that cause a cell to leave the order, to deviate, to stop executing a programme that Evolution took millions of years to perfect. In a way, as in other diseases, humans fight a daily battle against their own bodies, or rather against the ignorance they have of their own bodies. And it will be the sum of large and small discoveries, many of them made by individuals who probably will not get down in history, that will enable us to understand the reason why the body, an almost perfect machine, lets itself to be misled, close its eyes, in an apparently suicidal inertia, to the transformation that is occurring inside it. Of course, the better one understands the biology of cancer, the closer we get to cure it.
Implications: the extracellular environment and intracellular cascades
Anyone who has worked in a lab with tumour cells obtained directly from a patient will have been faced with a paradox: the same cells that multiply endlessly inside the body normally die quickly when in culture, that is, they do not inherently possess the “elixir of life”. What happens is that malignant cells must, for some time and perhaps forever (although this claim is quite controversial), have outward signs that support their existence, in a peculiar interaction between what is still healthy in the body and what has already suffered what we call malignant transformation. This interaction depends on the activation of intracellular biochemical cascades known as signal transduction pathways. There are signal transduction pathways that are so important for the survival and proliferation of a cell that they are often recruited by tumour cells and become ultimately essential for the growth of the cancer, being permanently activated in malignant cells - either as a result of genetic changes in the tumour cell itself or as a result of signals of the environment in which the cell is located. This, however, means that potentially, we can eliminate a cancer by inhibiting such signal pathways. For this reason, the Cancer Biology Unit has been studying which signal pathways are essential for tumour initiation and maintenance. We believe that this will give us not only a better understanding of the disease but also the opportunity to develop new antitumour weapons that are more selective and effective.
The background
The Cancer Biology Unit comprises a group of researchers whose names can be found hereand who are involved in several projects. To understand what they are currently doing and what they will focus on in future, without tiring those who have been patient enough to read this far, I will give two quick examples of the research we have conducted in the past.
In many types of cancer, mutations of the PTEN gene, which is a tumour suppressor, leads to loss of PTEN protein expression. However, in a study published in the Journal of Clinical Investigation, in 2008, we demonstrated that the PTEN is inactivated in malignant cells from patients with T cell acute lymphoblastic leukaemia of (T- ALL-) due to non-genetic mechanisms. Although the gene shows no mutation, the PTEN crashes due to changes in the protein. This study revealed that there is another protein, called CK2, which is responsible for the PTEN inactivation process, which, fortunately, can be inhibited pharmacologically. That same year our work was awarded the Pfizer Prize for Basic Research of the Society of Medical Sciences of Lisbon, and the Pulido Valente Science Prize of the Foundation for Science and Technology (FCT). Two years later we published another study showing that this non-genetic PTEN inactivation by CK2 mechanism is not limited to T-ALL and that it extends to chronic lymphatic leukaemia (here).
Most of our projects focus on the role of interleukin-7 (IL-7), which is a factor produced by the microenvironment in which leukaemia develops, in the progression of T-ALL. In 2011 we demonstrated that IL-7 accelerates the process of tumour growth in an article published in Cancer Research journal, and in the same year we found out that about 10% of paediatric patients with T-ALL have mutations in the IL-7 receptor (IL7R) that lead to the permanent activation of certain signal transduction pathways that are essential for the viability and proliferation of malignant cells. This latest study was published in Nature Genetics, and was awarded the Pfizer Prize for Clinical Research in 2011, and the Prize for best article in Immunology 2012 by the Portuguese Society of Immunology, and led to a Congratulating Vote of the Parliament for the excellence of scientific research conducted in Portugal, thus acknowledging the work undertaken at the Cancer Biology Unit. The most recent recognition of the work carried out at our laboratory was this year by being awarded the Distinguished Services Silver Medal by the Ministry of Health.
Future(s)
Whereas awards and distinctions make us obviously very proud and honoured, and act as additional motivation, they would mean nothing if they were not linked to the future, because it is in the future that we actually work everyday. What projects do we have in hands, anyway? What future lies ahead? It is a multifaceted future, but with one single aim: for instance, we want to try to understand if the activation of signal transduction pathways regulated by PTEN and CK2 may have a prognostic value in acute leukaemia, namely using methodologies that are easily transferable to clinical practice. To this effect, we have been collaborating with the Haematology Department of HSM and the Flow Cytometry Unit of the IMM. We have been working and interacting with the Academic Medical Centre of Lisbon (CAML), involving different and complementary skills and forms of knowledge that are of paramount importance and that should be an increasingly structural component of our common future. Science is indeed the result of synergies and if done in isolation, it will languish. Many other forms of collaboration, such as with the Clinical Immunology, Molecular Immunology and Cell Biology Units, among others, and with institutions such as the Portuguese Oncology Institute (IPO), Capuchos Hospital and many international research centres, have been crucial to our work and will certainly continue to be so in future. That future also involves discovering new ways to regulate PTEN; understanding how microRNAs can accelerate or delay leukaemia in certain contexts; determining how the signal transduction pathways activated by mutated IL7R may differ or not from those activated by IL-7; identifying new oncogenes and tumour suppressors that are involved in T-ALL; disclosing whether they exist and, if so, what are the characteristics of the so-called stem leukemic cells in T-cell leukaemia that may explain the reason for resistance to treatment and relapse; or testing the antitumour effect in animal models of particular agents (e.g. against CH2).
Naïve thoughts
I wrote above that, ultimately, the goal of all our projects could be resumed to a single one. It is perhaps a bit naïve and I have already presented it in several ways: seek to better understand the biology of the disease so that knowledge can help us develop new therapeutic strategies. The Ancients new that music has the power to make the gods smile. Certainly, music has the power to make us smile. Therefore, I presume that the lifts of the Dana-Farber Cancer Institute continue to have inside them small coloured notes notifying those using them of the existence of music sessions to alleviate suffering. Meanwhile, we pursue our quest so that one day those small notes (and our own work) will no longer be necessary. Is this naïve? At the Cancer Biology Unit we like to face challenges and work daily to demonstrate that perhaps it is not.