In the body there are thousands of cells with DNA errors that could cause cancer but fortunately only rarely these DNA errors, called genetic mutations, lead to a complete cancer.
The researchers now indicate that the context is the key, according to a study that they publish in the magazine ‘Science’.
The standard explanation is that a certain number of genetic failures in a cell’s DNA is needed to take it to the limit.
But there are well-known cases in which the same set of mutations clearly causes cancer in a context, but not in another.
A good example is a lunar, since the cells that compose it are genetically abnormal and often contain a mutated version of the DNA of the BRAF gene which, when it is found in the cells located outside a mole, usually leads to a melanoma.
But the vast majority of polka dots will never become cancerous.
Scientists at the Monorial Sloan Kettering Center, in the United States, affirm that their results offer a new and important perspective on cancer training, which contrasts with conventional knowledge.
“The standard idea that has existed for decades is that basically two types of mutations in DNA are needed to have cancer: an oncogene activated and a tumor suppressor gene deactivated – explains Dr. Richard White, Medical-Scientist of Memorial Sloan Kettering
Cancer Center (MSK) that studies melanoma in the laboratory -. Once those two obstacles are overcome, cancer is formed. Now we have this thing – oncogenic competence – that adds a third layer to the mixture. ”
For its part, Dr. Arianna Baggiolini, principal author of the study and postdoctoral fellow in the Studer laboratory, explains that “DNA mutations are like a lit match: if you have incorrect wood or if the wood is wet, you can get a wet
Little spark but no fire. But if you have proper wood, and maybe some wood, everything burns “.
In this example, the Atad2 is the firewood.
The development of a drug that eliminates this firewood would be another way of treating cancer, as well as attacking DNA mutations. ”
HPSC techniques developed by the equipment to study melanoma can have extensive applications for personalized cancer treatment.
The White and Studer doctors are already using the technique to create cancer disease models of individual patients.
From the blood of a patient, they can obtain cells to manufacture HPSC.
Next, they can introduce specific mutations into these cells that characterize the patient’s tumor.
These genetically paired cells can be used to test a wide panel of drugs to see what the patient can benefit.
“With the HPSC, we can potentially create specific cancer models for each patient in any tissue of the body, be it the brain, the liver or other organ – says Studer– I really hope that this will become a routine part of the
medical care”.
Genetic mutations are the main drivers of cancer, but not all cells with these mutations become cancerous.
Researchers have learned that the cell context – in particular, the specific genes that are activated in this cell – collaborates with genetic mutations so that the cells can form a cancer.
Scientists call it “oncogenic competition”.
Aim to the levers that control which genes are activated in a cell offers potential opportunities to treat cancer.
To demonstrate that ATAD2, a modifier factor of chromatin, played a decisive role, scientists carried out additional experiments in those who eliminated or added Atad2.
When they eliminated ATAD2 in an zebrafish model prone to melanoma, the cells lost their ability to form tumors.
When they added it to MC cells, the cells won this ability.
This indicated the researchers that Atad2 was effectively a key lever of oncogenic competition.
Taking advantage of the large amount of clinical data available in the MSK and through The Cancer Genome Atlas, they could show that Atad2 is important in cancer: patients with high amounts of Atad2 have a significantly worse survival, suggesting that it plays an important role
In the determination of the result of DNA mutations as BRAF.
“We have long since we know that the cell context is important in the training of cancer,” says White. But it is greatly unknown how the context is combined with genetic mutations to promote cancer. ”
To reach that question, it was associated with the Development Biologist of MSK, Lorenz Studer, an expert in the creation and use of stem cells to study and treat diseases.
Thanks to the complementarity of the knowledge of it – and at the efforts of the Arianna Baggiolini postdoctoral scholar and the Graduate Student Scott Callahan – were able to investigate how the cancer genetics and development biology cooperate in cancer formation.
They have discovered that the formation of melanomas depends on something called “oncogenic competence”, which is the result of a collaboration between the mutations of the DNA of a cell and the particular set of genes that are activated in that cell.
The competent cells to form a melanoma are capable of accessing a set of genes that are normally closed for mature melanocytes (the cells that produce melanin produce and give color to the skin).
To access these blocked genes, cells need specific proteins acting as keys.
Without them, the cells do not form melanomas, even when they have DNA mutations associated with cancer.
The findings explain why some cells, but not others, can form a cancer, and offer potential therapeutic objectives that could one day help patients.
The collaboration project began more than a decade ago and began with an observation that Dr. White did when he was still a postdoc who studied melanoma on zebrafish.
They discovered that only the fish with BRAF activated in the NC and MB stages were capable of forming tumors (what researchers call “oncogenic competition”).
Instead, the cells with BRAF activated at the MC stadium formed moles.
The result was surprising.
But what is true in fish is not necessarily in humans.
So, to expand these results, he was associated with Dr. Studer to perform similar experiments in human cells.
In this case, they introduced the BRAF mutated gene into the HPSC in the same three stages that were studied in the fish, and then implemented these cells in mice to see what they were capable of forming tumors.
Once again, only the first two stadiums -cn and MB- were able to form tumors consistently.
Animated by these results, they went further to investigate a possible mechanism.
Using what is called “molecular profile”, they compared the differences between the active genes in the three stages, both in the tumors of the zebrafish and in the human stem cell derivatives.
From this comparison, they could see that a key difference was a particular protein, Atad2, which was active in NC and MB cells, but not in MC cells.
The cells containing Atad2 can activate a single set of genes that are normally only seen in embryonic development, while those that do not have can not do so.
So atad2 is the key that opens these genes.
