Not only breast cancer: mutations in the BRCA gene, which are especially common among Ashkenazim, increase the risk of various types of cancer – also in men. The institute’s scientists reveal how they turn healthy cells in their environment into collaborators
Bullying, unfortunately, is a contagious behavior. This rule applies not only in the school yard or in the neighborhood, but also in the local playground. This understanding led the team of researchers in the laboratory of Dr. Ruth Shertz-Shovel, from the Department of Biomolecular Sciences at the Weizmann Institute of Science, to focus not only on the bullying of the cancer cells themselves, but also on their negative effect on the cells that surround them, which are part of the “microenvironment” of the tumor. These non-malignant cells can become cancer’s collaborators or its bitter enemies, and they are currently the focus of attention of laboratories around the world. In a new study, published recently, the Institute’s scientists revealed how gene mutations BRCAwhich oil has been implicated in many cases of breast cancer, adversely affect an important subset of cells in the pancreatic cancer microenvironment and impair the immune response against it.
to the garden BRCA In its form, it played an important role in the cell, as it has a part in the repair mechanism of damages that may be caused to our DNA. One out of every 40 Ashkenazi Jews and one out of every 400 in the general population are born with a gene BRCA that has undergone small changes (mutations) that impair its function and increase the risk of developing cancer. Although they are known mainly to women who perform preventive screening tests for breast or ovarian cancer, it was found that the mutations in the gene BRCA increase the risk of other cancers among men as well, for example in the prostate and pancreas. However, the awareness of this and the rates of testing among them are low.
The new study focused on a common type of pancreatic cancer, Pancreatic Ductal Adenocarcinoma (PDAC), which is extremely aggressive and largely incurable, with a survival rate of only 10% five years after diagnosis. In previous studies it was discovered that cancer cells succeed in harnessing and even changing the structure and function of cells in their environment called fibroblasts – fibrous cells that form the scaffolds that keep the body’s cells in place. However, an important question that remains open is whether and how cancer mutations are different, for example gene mutations BRCA, influence each in its own way on the reprogramming of these cells, which may constitute up to 90% of the cancerous tissue. Using samples collected from patients with pancreatic cancer, in collaboration with the Memorial Sloan Kettering Cancer Center in New York, Dr. Schertz-Shouvel and her team set out to check if mutations in the gene BRCA A unique negative effect on the fibroblast population in cases of pancreatic cancer.
Although they are known mainly to women who perform preventive screening tests for breast or ovarian cancer, the mutations in the BRCA gene increase the risk of cancer in men as well
In recent years, it has become clear how diverse the fibroblast population is and consists of many subpopulations. With the help of innovative research methods, the researchers, led by Dr. Lee Shashua, Dr. Aviad Ben-Shamuel and Dr. Marev Pevzner-Fisher from Dr. Shertz-Shovel’s group, mapped the differences between the different fibroblasts both in tumor tissues taken from patients with a gene mutation BRCA and from tissues taken from patients without a mutation in this gene, and found significant differences in the composition of the fibroblasts in each of the groups. Moreover, the research team discovered that a certain type of fibroblasts, containing the protein clastrin, was significantly more common in pancreatic cancer tumors with a mutation in the gene BRCA. In the past, it was discovered that the overactivation of clusterin – an umbrella protein (chaferon) that helps other proteins in the cell to perform their functions correctly – may contribute to the development of pancreatic cancer tumors.
Using cell cultures, including 3D tissue cultures (organoids) and a pancreatic cancer model in mice, the researchers showed that damage to the gene BRCA In the cancer cells, it affects the composition of the fibroblasts adjacent to them, even though the fibroblasts themselves do not contain the mutation. The researchers also revealed the mechanism responsible for the increased rate of fibroblasts with clusterin in tumors with a mutation in the gene BRCA: the protein HSF1 which is a central component in the cellular response to stress conditions, i.e. conditions that lead to the destruction of proteins. In previous studies, some of which were carried out in Dr. Shertz-Shovel’s laboratory, it was already discovered that this protein may play a central role in the transformation of fibroblasts into cancer-supporting cells.
When the researchers silenced the garden BRCA in cancer cells in a way that simulates the loss of function as a result of the mutations, and tested what happens in a cancer model in mice and in tissue cultures, they discovered that the fibroblasts underwent a change and significantly suppressed the activity of the T cells of the immune system, which were supposed to fight cancer. At the same time, the researchers identified a structural change in the fibers produced by the fibroblasts: in the tumors in which the gene BRCA was active and normal, the fibroblasts produced strong fibers arranged in parallel and woven into a dense network, while in inactive tumors BRCA, The fibroblasts will produce less branching and parallel fibers. These findings indicate that in pancreatic cancer with a mutation in the gene BRCA There is a marked decrease in the function of the fibroblasts as the producers of the fibers of the intercellular environment, and instead they suppress the response of the immune system and thus contribute to the development of the tumor.
On the way to new drugs
The cells of our body all work by virtue of the same genetic code, but this code is expressed in a completely different way in different types of cells, tissues and organs. The differences between the different types of cells are made possible thanks to changes and additions to the DNA molecules, which are used by the cell as punctuation marks when reading the genetic code and producing proteins according to it. These signs will determine, for example, whether to increase the production of a certain protein (perhaps similar to an exclamation mark) or whether to approach and read a certain gene at all (like colons guiding us to read a list). These changes and additions to DNA have been studied more closely in recent decades, within a field called “epigenetics” (literally: above genetics).
In another study, recently released from Dr. Schertz-Shovel’s laboratory, the researchers focused on the epigenetic mechanisms that may harness fibroblasts to support the cancer cells. In the study, led by Coral Halperin and in collaboration with the German Cancer Research Center, the scientists showed in a mouse model of breast cancer that the cancer cells Epigenetic changes in the adjacent fibroblasts. These changes cause the cells to express certain genes and produce proteins that support the cancer growth, unlike healthy tissue. The researchers found a correlation between these changes and an increase in the presence of the protein RUNX1whose production is increased in the fibroblasts of cancer patients and may be the one that carries out the epigenetic changes.
The cells of our body all work by virtue of the same genetic code, but this code is expressed in a completely different way in different types of cells, tissues and organs. The differences between the different types of cells are made possible thanks to changes and additions to the DNA molecules, which are used by the cell as punctuation marks when reading the genetic code
“The treatment of cancer has been undergoing a revolution in recent years,” says Dr. Shertz-Shouvel, “with the introduction of immunotherapy treatments – drugs that enlist the immune system in a targeted attack on the cancer cells. I hope that it will be possible to harness the knowledge that we and other researchers have gathered, such as the identification of subpopulations in the cancer’s microenvironment that suppress the immune response against it and the proteins that are involved in turning fibroblasts into cancer supporters, in order to open the door to new drugs, which along with immunotherapy treatments will eliminate them in a targeted manner Also the collaborators of cancer.”