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Researchers at the Vall d'Hebron Research Institute (VHIR) —which belongs to the Catalan Oncology Network (Oncocat) — have discovered a new cellular signaling mechanism that was previously unknown. It is the coordinated use of two languages used by the cell to send internal signals in a precise and targeted way. This mechanism does not replace existing forms of known communication (phosphorylation), but complements them. The finding is highly valuable biologically because this mechanism appears to have remained unchanged throughout the evolutionary scale, as it is present in everything from the simple worm, through flies, reptiles, small mammals and primates, to humans.

The mechanism is based on the methylation of components of the RAS-ERK pathway, one of the key pathways in many important biological processes and, by definition, a key to cell malignancy. Therefore, this research could have important implications for cancer "to the point that we could be facing a whole new era in the study of drugs capable of modulating the biological response induced by a signaling pathway," says Dr. Juan Ángel Recio, head of the Laboratory of Animal Models and Cancer at VHIR and coordinator of the study published today in the journal Science Signaling.

With cancer, to give a simplified example, cells lose control. All of the mechanisms that regulate, organize and force them to make up the tissue in question stop working. They don’t die. They don’t commit suicide. They don’t differentiate themselves. In fact, they become immortal. This new signaling mechanism may provide answers to some of the questions previously known signaling pathways left unanswered. In some cases, methylation could be key to stopping the proliferation of this loss of control and, above all, could be key to guiding the cell back towards differentiation. “When that happens, tumor cells could become a mere nodule,” explains Dr. Recio, “meaning that this new, previously undiscovered, level of regulation could lead us to identify new targets and new therapeutic strategies that would intervene on a level we have never seen before and this, with all the weapons we have today, could be a great breakthrough in the fight against cancer and other diseases.”

Why is the RAS pathway key to cancer?

The RAS genes are coded by a group of proteins also called RAS, which work as a chain of molecular switches to regulate a number of signaling pathways within the cell. These pathways control such important cell functions as proliferation, differentiation, adhesion, migration and death. Whether or not these pathways function correctly and control the cell depends on the mutations the gene suffers, which can lead the cell into malignant processes.

The signaling mechanisms that regulate all of these pathways and give them the green light or not, thus regulating their responses, function through phosphorylation and this was the cell language known up to now. These proteins have a specific combination of nucleosides that allow for chemical reactions that unite with or liberate phosphate. Thus the activated forms incorporate phosphate, making it a green light. All of this regulates this pathway using external signals that the cell receives through its membrane (growth factors), which is what sends the signal to the cell telling it what to do at all times (divide, die, differentiate, etc.). When there are mutations in this pathway (which is very frequent in cancers) the orders to cells are aberrant and growth is uncontrolled.

This pathway has always been the focus of many cancer treatments. Blocking this pathway yields clear results in reducing tumors but precisely because it is so important, the lack of therapeutic targets specifically directed at the mutated genes that alter this pathway, or at specific proteins in the chain, leads to a wide range of side effects.

What does the discovery of methylation of the RAS pathway mean?

Methylation could explain why, despite common activation of this pathway, different growth factors lead to different biological responses. What hadn’t been explained previously was how activation of the same signaling pathway, by different external stimuli (growth factors) and signal transduction through activation/deactivation processes (phosphorylation and dephosphorylation), determined different biological functions or, even, opposing biological results.

The existence of a different and parallel language, methylation, which acts in coordination, modulating the RAS pathway and depends on the activation of the chain, allows us to understand why these biological responses are so varied, ehy the cell can give contradictory orders and how this complementary pathway is regulated. It is as if in addition to a network of traffic lights, there were also yield and stop signs.

These findings also explain why MTA (a molecule the body generates naturally through metabolism and, thus, is well tolerated) has antitumor cytostatic effects (inhibiting cell growth). “Now we understand it all”, explains Dr. Recio. “Our group has seen that this molecule is able to block methylation of one of the kinase enzymes in the signaling pathways. This works as a valve controlling the global activation flow, thus changing the cell fate induced by growth factors in the tumor environment and inhibiting tumor growth. This reaffirms this pathway as a candidate for a new type of intervention in the search for therapeutic targets.

Biology itself has determined the importance of this cell-communication language, as it has remained unchanged throughout the evolutionary scale. Preliminary findings, though as of yet unproven, seem to indicate that this regulatory mechanism has been incorporated evolutionarily at a sequence level in at least one of the members of the different kinase families of the human kinome with many diverse functions. Meaning it is as if each important body function this language is involved in (methylation) ensures that at least one element of this family can serve as an interpreter. 

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