Blocking the METTL3 protein can increase sensitivity to chemotherapy in neuroblastoma, according to research from the University of Gothenburg. The study shows how specific RNA modifications affect gene expression in the early development of neuroblastoma.
The studies were conducted on mice, and the results have been published in the EMBO Journal. While the research focuses on the mechanisms behind neuroblastoma, it could be the starting point for more clinically focused investigations.
"The METTL3 protein could be used as a drug target to develop efficient inhibitors that may reduce tumor growth and enhance the effectiveness of chemotherapy in patients with neuroblastoma," says Tanmoy Mondal, a researcher at the University of Gothenburg who led the study.
Neuroblastoma is a type of cancer that develops in peripheral nerve tissue and primarily affects young children. The severity of the disease can vary greatly. Many cases resolve on their own, but some children develop a form that is highly resistant to treatment and carries a poor prognosis.
New potential treatment for high-risk neuroblastoma
The study suggests that inhibiting METTL3 could be a new treatment strategy for high-risk neuroblastoma, especially for cases that are resistant to current therapies.
The METTL3 protein was found to play an important role in neuroblastoma by altering the expression of certain genes that control cell growth. By blocking METTL3, a protein that regulates m6A RNA modification, the researchers were able to promote cancer cell differentiation, making the cells more receptive to treatment. The increased differentiation meant the cancer cells started behaving more like normal cells.
When drugs that inhibit METTL3 were combined with chemotherapy, the researchers observed greater tumor shrinkage in the mice compared to those that received only chemotherapy.
Mature nerve cells
The study explores how RNA modifications influence cancer cell behavior. It shows that METTL3 modifies HOX genes in a way that promotes an undifferentiated and aggressive cancer state. HOX genes are involved in the differentiation of nerve cells, helping stem cells develop into mature nerve cells. In neuroblastoma, the expression of these genes is often disrupted.
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"By blocking METTL3, we were able to reverse this process, allowing cancer cells to differentiate and lose their aggressive characteristics. This could be especially valuable in treating MYCN-amplified neuroblastoma, a form of the disease associated with poor outcomes," says Ketan Thombare, doctoral student at University of Gothenburg and one of the lead authors.
Despite the promising results of the study, more research is needed to determine how METTL3 inhibitors can be used in clinical settings.
"We are hopeful that our research will pave the way for new clinical trials and, eventually, new treatments that can save lives," says Roshan Vaid, another lead author in the study and postdoctoral research fellow at University of Gothenburg.
The study was conducted in collaboration with researchers from research institutes in Sweden as well as in Germany, United Kingdom and South Korea.
Article: : METTL3/MYCN cooperation drives neural crest differentiation and provides therapeutic vulnerability in neuroblastoma; https://doi.org/10.1101/2023.10.06.561194
