Researchers at the Spanish National Cancer Research Centre (CNIO) have discovered a genetic alteration that is directly involved in at least 10% of cases of one of the most common cancers in children, T-cell acute lymphoblastic leukaemia. In a paper published this week in the printed edition of Genes and Development, the scientists explain how the mice in which a specific gene, known as Capicua, has been inactivated, inevitably develop this type of leukaemia.
They have also discovered that, in mice in which Capicua ceases to function, a type of drug, MEK protein inhibitors – such as trametinib– which are already being used to treat various types of tumours and in trials against many others, no longer work. This information may help us to understand why these treatments are not effective in certain patients. The study has been co-directed by Mathias Drosten, and Lucía Simón-Carrasco is the lead author.
The vast majority of tumours are caused by mutations in various genes. Knowing each and every one of the genetic factors involved in cancer – even those that appear mutated in relatively few types of cancer– is essential, in order to discover the individual features of each tumour. This is the only way to develop more effective personalised therapies.
Therefore, identifying a gene that plays a key role in 10% of the cases of a certain type of cancer – a fairly high incidence– is very relevant. "Especially taking into account that inactivating Capicua is enough to trigger the appearance of T-cell tumours, at least in mice," says Drosten.
T-ALL mouse model with inactivated CIC/CAPICUA (staining with CD3 antibodies highlighting aberrant T cells)./ CNIO
CAPICUA IS A COMPONENT OF A CANCER HIGHWAY
The CNIO researchers focussed on Capicua while decoding one of the most important biochemical signal highways for cells, the so-called RAS-MAPK pathway. Scientists from all over the world have been studying this pathway for decades to understand how the signals are transmitted from molecule to molecule and why, if there are any failures, a type of cancer often develops.
As Drosten explains, it has been found that RAS-MAPK has a first section that is "quite linear", in which each signal activates the next one, but at some point the trunk branches out and a tree of signals appears. More than a hundred genes are known that play a role in this stage, and Capicua is one of them.
The CNIO Group focused their attention on this gene because it frequently appears mutated into different types of cancer. It was originally discovered, and named Capicua, in its version found in fruit flies. The name refers to the origin of the word in Catalonian, cap-i-cua (head and tail), since the heads of the embryos of the fly that have the mutated gene are directly connected to their tails, without the rest of the body. The function of this gene in mammals, where it is usually called CIC, is not well known.
Simon-Carrasco and his colleagues developed a mouse model at the CNIO to study what happens when they inactivate CIC/CAPICUA. The most striking result was the development of T-cell acute lymphoblastic leukaemia (T-ALL) in the animals. This is the first time it has been found that the inactivation of Capicua in adult mice inexorably leads to the formation of T-ALL tumours, a relationship never suspected previously.
To verify the relevance in humans of this result, the researchers analysed T-ALL tumour samples, and indeed found that the Capicua gene appears mutated in at least 10% of them.
Given that the inactivation of Capicua is what generated acute lymphoblastic leukaemia, this gene acts as a tumour suppressor. The pattern of mutations previously observed in cancers in which Capicua appears mutated already pointed to this function, but this is the first time that the hypothesis has been confirmed experimentally. Knowing that Capicua is a tumour suppressor provides many clues to understanding what it does exactly in other tumours.
One of the findings of the paper may also have therapeutic relevance in the short term. The researchers have discovered that the tumours in which Capicua appears inactivated do not respond to drugs that act via the RAS-MAPK pathway. It seems to work as a resistance system: the drugs act as the brake pedal, but there is no effect if the brake pads (Capicua) are damaged.
"Many tumours are treated with drugs that affect the RAS-MAPK pathway; therefore, if we know that Capicua is involved in their level of effectiveness, we will be able to know which patients are more likely to develop resistance to these treatments," says Lucia Simón-Carrasco.
WHY THE INACTIVATION OF CAPICUA INDUCES TUMOURS
The study also provides clues about the relationship between Capicua and the formation of tumours. Capicua directly represses the ETV4 gene, which has oncogenic potential; when Capicua is inactivated, the expression of ETV4 increases. When the researchers removed the functions of Capicua and ETV4 simultaneously, they noted an almost complete inhibition regarding the formation of T-ALL tumours.
"This is the first direct evidence available about the way in which the inactivation of CIC causes the formation of tumours," says Simón-Carrasco.
"A better understanding of the molecular events triggered by the inactivation of Capicua should provide more effective therapeutic approaches," the researchers conclude in their paper.
The study has been conducted in collaboration with Gerardo Jiménez, ICREA researcher at the Institute of Molecular Biology in Barcelona, and Alejandro Gutierrez, from Harvard University. It has been funded by the Fundació La Marató de TV3 (20131730/1), the European Research Council (ERC-AG/ 250297-RAS AHEAD), the EU-Framework programme (HEALTH-F2-2010-259770/LUNGTARGET, HEALTH-2010-260791/EUROCANPLATFORM), the Ministry of Economy and Competitiveness (SAF2014-59864-R), the Autonomous Community of Madrid (S2011/BDM-2470/ONCOCYCLE) and the Spanish Association against Cancer (AECC) (GC16173694BARB).
Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma. Lucía Simón-Carrasco, Osvaldo Graña, Marina Salmón, Harrys K.C. Jacob, Alejandro Gutierrez, Gerardo Jiménez, Matthias Drosten, Mariano Barbacid. (Genes and Development 2017). DOI: 10.1101/gad.300244.117