In further experiments, the researchers discovered that BRCA silencing in cancer cells induced a shift in the function of adjacent fibroblasts, causing them to start suppressing the immune system’s T cells. The researchers also identified a structural change in the fibers produced by the fibroblasts: In tumors with an active, unmutated BRCA gene, fibroblasts generated tough fibers forming a dense meshwork, whereas in tumors lacking BRCA activity, fibroblasts produced branching and softer fibers.
These findings suggest that in pancreatic tumors harboring BRCA mutations, the action of fibroblasts as producers of fibers for the intercellular environment is significantly reduced. Instead, they act as immune response suppressors, thus contributing to the malignant tumors’ development.
Blazing the trail for new therapies
All the cells of our body operate in accordance with the same genetic code, but this code is expressed in an utterly different manner in different cell types, tissues and organs. The differences between the body’s various cells are due to changes and additions of modifications to the DNA. The modifications function as punctuation marks enabling the cell to read the code correctly and produce proteins accordingly. These marks determine, for example, whether to increase production of a certain protein (perhaps similar to the role of an exclamation mark) or whether to even read a certain gene at all. Such changes and additions to DNA are being studied closely in a field called epigenetics (Greek for “above genetics”).
In another study by Scherz-Shouval’s lab, the scientists focused on an additional aspect of fibroblast conversion into “bullies”: epigenetic mechanisms employed by cancer cells for the rewiring of fibroblasts. In this study, led by Coral Halperin from Scherz-Shouval’s lab, in collaboration with Dr. Joschka Hey from Prof. Christoph Plass’s lab at the German Cancer Research Center (DKFZ), the team showed, in mouse models of breast cancer, that cancer cells induce epigenetic alterations in normal fibroblasts. As a result, unlike what happens in healthy tissue, these fibroblasts change their expression of certain genes and produce cancer-assisting proteins. The researchers also found a correlation between these changes and an elevation in the levels of a protein called RUNX1: Its production also increased in fibroblasts of cancer patients, and its activation could be responsible for the epigenetic alterations.
“The treatment of cancer has been revolutionized in recent years with the introduction of immunotherapy – drugs that recruit the immune system in a targeted attack on cancer cells,” says Scherz-Shouval. “Hopefully, the knowledge that we and other researchers have gathered – including the identification of immune-response-suppressing fibroblast subtypes, and of the proteins involved in turning fibroblasts into cancer promoters – can be harnessed for developing new drugs. Such drugs, alongside immunotherapeutic treatments, would effectively target not only cancer cells, but also their collaborators.”