Researchers from Uppsala University have discovered the protein that makes tumour cells insensitive to medulloblastoma radiation treatment and causes relapse.
Medulloblastoma is a malignant brain tumour that often becomes resistant to therapy and leads to relapse. The researchers believe their findings could lead to better treatment for children, who have the highest risk of relapse.
Medulloblastoma is the most common form of a malignant brain tumour in children. The disease is often cured with surgery, radiation, and chemotherapy. However, a distinct type of medulloblastoma has an increased risk of becoming resistant to treatment. This can cause recurrence that is strongly connected to increased mortality.
Understanding medulloblastoma on a cellular level
The fact that certain cancer cells can avoid radiation treatment suggests that there are biological factors inside cancer cells that can enhance their resistance.
The researchers found that certain cells within the tumour bulk did not divide as often as other cancer cells did, this made them less sensitive to irradiation. The researchers also found that an accumulation of the protein, SOX9 was present in recurrent samples from patients who had been operated on before and after their relapses. This caused the research team to suspect that SOX9 was involved in the recurrence process.
“We found that a stem cell protein called SOX9 was present with high activity in rare cells in the tumours and that cells with high activity of SOX9 were resting. SOX9 protected the resting cancer cells against radiation by temporarily inhibiting another protein that otherwise promotes cell division,” explained said Fredrik Swartling at Uppsala University, who led the study.
“In experiments where we knocked out SOX9 with the CRISPR/Cas9 genetic scissors, tumour cells lost their capability to relapse, which suggests that SOX9 is important for this process,” added Swartling.
Reprogramming cells to improve treatment
The researchers analysed animal models that resembled the relapse in patients. They observed that SOX9 caused increased migration and metastases of cancer cells in areas within the spinal cord. They also noticed that cancer cells became reprogrammed to avoid recognition by the immune system. It was therefore established that these were contributing factors in the cause of relapse.
The researchers continued to examine how the substances that inhibited SOX9 influenced the development of relapses in animal models. The team used bioinformatic analysis to discover several drugs that could be used to treat medulloblastoma and had a suppressing effect on SOX9 relapses.
“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,” said Anna Borgenvik a postdoc in the research group who performed the treatment studies based on the bioinformatic analyses developed by Holger Weishaupt, another researcher on the study.
