Now your body has thousands of cells lurking in DNA mistakes that can cause cancer. However, in rare cases, these DNA mistakes, called gene mutations, can lead to serious cancer. Why?
The standard explanation is that pushing a cell out of the edge requires a certain number of genetic “hits” in the cell’s DNA. However, there are well-known cases where the same series of mutations clearly causes cancer in one situation and not in another.
A good example is a mole. The cells that make up the mole are genetically abnormal.Quite often, they contain mutated DNA versions BRAF A gene that often causes melanoma when found in cells outside the mole. However, the vast majority of moles never become cancerous. It’s the challenge that scientists are looking to the context of cells for clues to explain the differences.
Target context, not just mutations
Scientists say their results provide an important new perspective on cancer formation, as opposed to traditional knowledge.
“The standard idea that has existed for decades is that basically two types of DNA mutations are needed to develop cancer: an activated oncogene and an ineffective one. It’s a tumor suppressor gene, “says Dr. White. “Clearing these two hurdles creates cancer. This gives us something completely different: carcinogenicity and adds a third layer to the mixture.”
Dr. Baggiolini, the lead author of the study and a postdoc at the Studer lab, likens this situation to the onset of a fire. “A mutation in DNA is like a lit match. If you have the wrong tree or the tree is wet, it may flicker a little but not ignite, but the correct tree Yes, and if it’s probably on fire, everything burns out. “
In this example, ATAD2 is kindling. Developing drugs to remove this kindling would be another way to treat cancer, in addition to targeting DNA mutations.
Techniques with future potential
The hPSC technology developed by the team to study melanoma may prove to have widespread use in personalized cancer treatments. Already a doctor. White and Studer use this technique to create a disease model of cancer in individual patients. From the patient’s blood, cells can be obtained to make hPSC. The specific mutations that characterize the patient’s tumor can then be introduced into these cells. These genetically matched cells can then be used to test a large number of drug panels to see which one benefits the patient. You can then return these drugs to zebrafish to see that they actually work in living animals. Researchers believe that this transfer between cells in the dish and animal studies gives the patient the best chance of finding a drug that works.
“With hPSC, we have the potential to create patient-specific disease models for cancer in various tissues of the body, including the brain, liver, and other organs,” said Dr. Studer. “I really want this to be part of my daily care.”
It’s no coincidence that these widespread results are the result of a steady decade of collaboration between two labs with different expertise. “It’s becoming a cliché that science is better at collaborating, but in this case it was really important,” says Dr. White.
“Everyone wants science to go fast. We want science to go fast, but sometimes science has to be slow to reach the core truth.”
To prove that ATAD2 plays a decisive role, scientists conducted additional experiments to remove or add ATAD2 again. When scientists removed ATAD2 in a melanoma-prone zebrafish model, the cells lost their ability to form tumors. The cell gained this capacity when they added it to the MC cell. This told researchers that ATAD2 is actually an important means of carcinogenic potential.
The vast amount of clinical data available through MSK and The Cancer Genome Atlas can be used to show that ATAD2 is important in cancer. Patients with high levels of ATAD2 have significantly poorer survival and are the result of DNA mutations such as BRAF..
“We’ve known for some time that cell status is important for cancer formation,” said Richard White, a physician scientist at the Memorial Sloan-Kettering Cancer Center, who studies melanoma in the lab. .. “But to be exact how The context is Genetic mutation Little is known about promoting cancer. “
To answer that question, Dr. White worked with MSK developmental biologist Lorenz Studer. This is an expert in creating and using stem cells to study and treat diseases. With their complementary expertise and the efforts of postdoctoral fellow Arianna Baggiolini and graduate student Scott Callahan, they were able to investigate how cancer genetics and developmental biology work together in cancer formation. rice field. Ten years later, the results are in.
In a treatise published on September 3, 2021 Chemistry, Dr. White, Studer, and their team report that melanoma formation depends on what is called “carcinogenic potential.” This is the result of a particular set of collaborations with intracellular DNA mutations. gene It is turned on in that cell. Cells capable of forming melanoma have access to a set of genes that are normally closed to mature melanocytes, the cells that produce melanin and color the skin. To access these locked-up genes, cells need specific proteins that act as keys. Without them, cells do not form melanoma, even with cancer-related DNA mutations.
Findings provide an explanation for why some cells can form but others cannot. cancer, And one day it provides a potential therapeutic target that can help the patient.
From fish to humans
The collaborative project began more than a decade ago, with observations made by Dr. White when he was a postdoc still studying zebrafish melanoma. These small fish are great for studying the development of melanoma. See the tumor growing under the fish scales, And it is easy to get rid of the tumors and study them at the molecular level.
“Looking at these zebrafish melanomas, we found that there are more active genes that are characteristic of embryonic cells than mature melanocytes,” says Dr. White. “I was curious why these genes were turned on. Are they important for the development of melanoma? If so, how?”
To answer this question, Dr. White and his team genetically modified it to contain mutated zebrafish. BRAF Gene — The same as found in about half of melanomas.They are BRAF Genes: Neural Crest Stage (NC), Melanocyte Blast Stage (MB), and Melanocyte Stage (MC) in such a way that they are turned on at three different stages of melanocyte development in different fish. These stages refer to the state of cells that gradually differentiate. (It can be thought of as a stage similar to melanocyte kindergarten, elementary school, and high school.) Next, the fish were grown and the tumor was observed.
After a few months, they BRAF When activated at the NC and MB stages, it was able to form tumors (what researchers call “carcinogenic potential”).Cell BRAF Instead, it was activated at the MC stage to form moles.
The result was impressive. However, what applies to fish does not always apply to humans. So, to extend these results, Dr. White worked with Dr. Studer to perform a similar experiment on human cells.Dr. Studer’s team Previously shown Human pluripotent stem cells (hPSCs) can be used to perform each of the three stages of melanocyte development.In this case, they mutated BRAF The genes were introduced into the hPSC at the same three stages that were studied in fish, and then these cells were transplanted into mice to see which ones could form tumors. Again, only the first two stages (NC and MB) were able to consistently form a tumor.
What controls “ability”?
Encouraged by these discoveries, researchers investigated further possible mechanisms. They used what is called “molecular profiling” to compare active gene differences in three stages for both zebrafish tumors and human stem cell-derived tumors. From this comparison, they confirmed that the key difference was the specific protein ATAD2, which was active in NC and MB cells but not in MC. cell..
ATAD2 is a so-called chromatin modifier. It can bind to regions of the chromosome near the genes and turn them on (technically, they are transcribed into messenger RNA and translated into proteins). Proteins like ATAD2 alter the cell’s “epigenome” (the way DNA is packaged and spooled inside the cell) rather than the “genome” that is the sequence of the DNA itself. Cells containing ATAD2 can turn on their own set of genes, which is normally found only in embryogenesis, but cells without ATAD2 cannot. In other words, ATAD2 is the key to unlocking these genes.
Arianna Baggiolini et al, the developmental chromatin program determines the carcinogenic potential of melanoma, Chemistry (2021). DOI: 10.1126 / science.abc1048
Memorial Sloan Kettering Cancer Center
Quote: Why are only some cells capable of forming cancer?For scientists, the context obtained from https://medicalxpress.com/news/2021-09-cells-cancer-scientists-context-key.html on September 2, 2021 is important (September 2, 2021). Sun)
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