Devel Cell: Why aren't some tumors responding to therapy? The culprit is: fibroblasts!

4, 2020 /PRY/ -- In a recent study published in the international journal Developmental Cell, scientists from the Sanford Burnham Prebys Institute for Medical Discovery and others said molecular changes in fibroblasts may help explain why a type of colon cancer does not respond to therapy, and that fibroblasts can support tissue throughout the body; targeting these cells may help develop new ways to make cancer therapy more effective. In the
paper, researchers analyzed the characteristics of fibroblasts in CMS4 colorectal cancer, one of the most malignant and difficult-to-treat colorectal cancers, to determine how these cancer-related cells obtain traits that promote cancer that supports nearby cells, and CMS4 affects the health of nearly one-third of colorectal cancer patients.
researcher Jorge Moscat-Guillen said: 'This study is made up of two important components: first, we showed in a mechanical way how these cancer-related fibroblasts get the characteristics they have, and second, we confirmed that the findings in the laboratory model apply equally to patients and begin to reveal how these results are applied clinically.'
Photo Source: Sanford Burnham Prebys Medical Discovery Institute tumor tissue is not just made up of cancer cells, it also contains several other types of cells that affect tumor behavior and have a profound effect on whether the tumor responds to therapy, including immunotherapy.
fibroblasts are spread throughout the body, in the colon, as part of the body's contraction system, which is critical for digestion, and now researchers have known that the presence of fibroblasts in tumors can affect their behavior, particularly the tumor's response to immuno-checkpoint blocker drugs that lift the immune system's brakes and promote its attack on cancer cells.
so far, one of the unresolved questions in the field is what causes these fibroblast-filled tumors to continue to progress. In previous studies, researchers have developed a mouse model that simulates CMS4 colorectal cancer, and like this type of colorectal cancer, researchers have found high concentrations of cancer-related fibroblasts in these mice' tumors.
researcher Moscat said: 'In the current study, we used mouse models, cells grown in the tube and organoids to clarify the association between cancer cells and cancer-related fibroblasts, and found that cancer cells can send signals to change the properties of fibroblasts, the appearance of fibroblasts will make tumors more aggressive and more hidden from the immune system.'
this molecular switch is able to remove levels of the PKCz protein, thereby increasing the levels of the sox2 protein in fibroblasts, which seem to make fibroblasts friendly to promoting tumor growth.
The researchers then used animal models to detect the behavior of altered cells in the lab, using single-cell RNA sequencing techniques to confirm that the results observed in the lab were consistent with those observed in patient samples; Communication, fibroblasts can play a role in a way to protect tumors from immune system sniping, and then researchers want to find ways to target the tumor to protect the environment of fibroblasts, in addition, these drugs can be used in combination with immunotherapy to reduce the defense of fibroblasts, and promote the checkpoint blocking the drug-activated immune cells to play a role.
'Now that we understand the roles of SOX2 and PKCz, we have two better biomarkers to conduct clinical trials on patients, ' said Diaz-Meco, a researcher at the end of the study. 'The results of this paper may be applied to other types of cancer, especially pancreatic cancer, which contains a large number of fibroblasts that appear to make tumors resistant to therapy.'
() Original source: Hiroaki Kasashima, Angeles Duran, Anxo Martinez-Ordoñez, et al. Stromal SOX2 Upregulation Promotes Tumorigenesis through the Generation of a SFRP1/2-Expressing Cancer-Associated Fibroblast Population, Developmental Cell (2020). DOI:10.1016/j.devcel.2020.10.014。