Scientists find that a protein associated with neurodegenerative diseases is also linked to childhood brain cancer

A protein widely studied due to its association with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) is also linked to medulloblastoma, a type of central nervous system cancer. Medulloblastoma is one of the most common and aggressive brain tumors in children, arising from undifferentiated cells during early neuronal development.

A study carried out by a group of Brazilian scientists showed in vitro and in vivo that the VAPB gene is linked to the cell proliferation of these tumors. An article on the study is published in the journal Scientific reports.

The discovery indicates a potential marker of severity and, upon further investigation, a future therapeutic target. Medulloblastoma is currently treated with a combination of surgery to remove the tumor and radiation and/or chemotherapy, both of which are aggressive and can cause lasting brain damage.

VAPB stands for vesicle-associated membrane protein B/C. Vesicle-associated membrane proteins (VAMPs) are a family of proteins that play crucial roles in cellular processes, including lipid metabolism and intracellular transport. They are expressed in all cell types but are particularly present in neurons.

In the study, high VAPB gene expression in medulloblastoma correlated with reduced patient survival. Tumor cell proliferation requires the protein, and an exacerbated increase can make the disease even more aggressive. On the other hand, knockout of VAPB using CRISPR/Cas9 gene editing delayed cell cycle progression.

“These results open new avenues for understanding the molecular bases of neurological diseases. The major novelty of the study is the link between this protein associated with neurodegeneration and the development of the tumor. Previous research has shown that it is expressed in breast cancer but nothing has been done. So far they have shown a link with central nervous system cancer,” said Oswaldo Keith Okamoto, professor at the Institute of Biosciences at the University of São Paulo (IB-USP).

Okamoto is co-corresponding author of the paper with Floris Foijer, a professor at the European Research Institute for the Biology of Aging at the University of Groningen in the Netherlands. He was also one of the thesis advisors of the first author, Amanda Faria Assoni, during her Ph.D. research.

The study was conducted at the Human Stem Cell and Genome Research Center (HUG-CELL). HUG-CELL is led by Mayana Zatz, professor at IB-USP and also co-author of the article.

“Expression of this protein is reduced in ALS, and this reduction causes degeneration. On the other hand, we found that high expression of VAPB in medulloblastoma correlated with reduced patient survival, and When we suppressed the expression of the protein in tumor cells, the cell cycle slowed down, but the cells did not die.”

“We have taken the first steps towards identifying some of the pathways impaired by the lack of VAPB, but we now need to better understand which pathways are most important,” Assoni told FAPESP Agency.

Statistics on medulloblastoma in Brazil are scarce, but experts estimate that cure is not achieved in about a third of all cases. Tumors of the central nervous system represent 20% of childhood cancers, mainly affecting children aged 5 years or younger, according to the National Cancer Institute (INCA).

In the entire Brazilian population, new cases of central nervous system cancer are expected to reach an average of 11,490 per year during the period 2023-2025, according to the INCA report “Estimativa 2023: incidência de câncer no Brasil”: 6,110 in men and 5,380 in women, corresponding to incidence rates of 5.8 per 100,000 men and 4.85 per 100,000 women. Worldwide, the number of cases of central nervous system cancer is approximately 310,000 per year (1.6% of all cancer cases).

Advanced techniques

In the study, researchers used tumor spheroids, three-dimensional models of cancer cell culture designed to mimic the in vivo environment. The spheroids used in the study came from medulloblastoma cell lines, including a line they recently developed from a patient’s tumor sample. Controls were neural progenitor cells derived from a human-induced pluripotent stem cell (hiPSC) line.

The researchers used RNA sequencing and CRISPR genome engineering to generate VAPB-free cell lines. In vivo tests were carried out on mice, but the study also involved the analysis of clinical data from 632 medulloblastoma patients, including gene expression and survival rates, available in a database scientist.

“Although VAPB is not generally linked to cancer, we detected alterations in several pathways classically studied in tumors in VAPB knockout cells. The cellular mechanisms in question are well tested and widely used as markers of cancer. aggressiveness. In my opinion, this discovery will stimulate research into other proteins related to types of cancer for which ideal treatments do not yet exist,” Assoni said.

An earlier study using laboratory-grown cell lines, led by Okamoto and published in the journal Brain research in 2020, molecules identified, including the OCT4 protein, could potentially serve as biomarkers for medulloblastoma.

“Many researchers study cancer around the world, but central nervous system tumors are less well studied because they are rarer than other cancers. Yet they are associated with high mortality, lack new treatments and “are important from a clinical point of view. Knowledge of CNS tumors will be very valuable for patients and their families,” Okamoto said.

Patient families created the Medulloblastoma Initiative in 2021 to raise funds for 13 research laboratories in the United States, Canada and Germany, known as the Cure Group 4 Consortium. An article co-written by members of the Consortium was published in the journal Nature describing a groundbreaking discovery that traces the origins of medulloblastoma to the development of a specific cell type.