Medulloblastoma, a kind of malignant brain tumor, can develop resistance to therapy, resulting in relapse. Uppsala University scientists found a protein that causes tumor cells to rest and become insensitive to radiation treatment. The researchers believe that the findings will ultimately result in improved treatments for children who are at high risk of relapse.
Medulloblastoma is the most prevalent type of malignant brain tumor in children, and it is generally curable with operation, radiation, and chemotherapy. However, a certain form of medulloblastoma is more likely to develop resistance to the treatment. This will result in recurrence, which is closely linked to increased mortality.
The fact that certain cancer cells are resistant to treatment shows that there are biological factors within cancer cells that can increase their resistance to treatments like radiation. The current study found that specific cells inside the tumor bulk did not divide as frequently as other cancer cells, making them less vulnerable to irradiation.
Investigators discovered an increase in a specific protein, SOX9, in recurring samples from individuals who had been operated on before and after developing a relapse. They suspected SOX9 of being involved in the recurrence process.
We found that a stem cell protein called SOX9 was present with high activity in rare cells in the tumors and that cells with high activity of SOX9 were resting. SOX9 protected the resting cancer cells against radiation by temporary inhibiting another protein that otherwise promotes cell division. In experiments where we knocked out SOX9 with the CRISPR/Cas9 genetic scissors, tumor cells lost their capability to relapse, which suggests that SOX9 is important for this process.”
Fredrik Swartling, Study Lead Author, Uppsala University
SOX9 enhanced cancer cell migration and metastases in regions of the spinal cord in animal models that mirrored recurrence in patients. Cancer cells were also altered to avoid detection by the immune system. These are factors that may contribute to relapse.
The effects of drugs that inhibited SOX9 on the occurrence of relapses in animal models were also investigated by scientists. They found a few medicines utilized for various therapies that surprisingly had a lowering effect on SOX9 in relapses using bioinformatic analyses.
We hope that our discovery could lead to more specific treatments against those SOX9 positive, slow dividing cancer cells. Eventually, it might improve the possibilities to treat children with medulloblastoma who have the highest risk of developing relapses.”
Anna Borgenvik, Uppsala University
Anna Borgenvik is a postdoc in the research team who carried out the treatment studies based on the bioinformatic analyses designed by Holger Weishaupt, an investigator in the group.
The research was a collaboration between the Preclinical Cancer Treatment Center, a SciLifeLab, and Uppsala University sponsored pilot facility.
Borgenvik, A., et al. (2022) Dormant SOX9-positive cells facilitate MYC-driven recurrence of medulloblastoma. Cancer Research. doi.org/10.1158/0008-5472.CAN-22-2108.