An international team of scientists, led by researchers at the University of California San Diego School of Medicine and the San Diego branch of the Ludwig Institute for Cancer Research, describe how the loss of a single gene can negatively impact neural development and promote rapid brain tumor growth.

Atypical teratoid rhabdoid tumors are a rare, fast-growing form of brain cancer that usually strikes children three years and younger, though they can occur in older children and adults.

There are multiple treatments but no definitive standard of care. Long-term survival is poor.

The cause of the tumors is primarily linked to inactivation of a gene called SMARCB1 – part of a larger complex that helps regulate gene expression and developmental processes.

The study, published Thursday, did not indicate whether anything might lead to the gene not activating.

“Previous research has established that, unlike some cancers, ATRT is predominantly associated with the functional loss of a single gene – SMARCB1 – which leads to tumor development through changes in how genes are expressed rather than the combined effect of multiple gene mutations,” said senior author Frank Furnari, professor of pathology.

“ATRT is a very deadly cancer with very few effective therapies, which are complicated by the negative effects of radiation upon the child’s cognitive development. We need targeted therapeutics and to create those, we need to better understand the mechanisms driving ATRT.”

Led by Furnari and first author Alison Parisian, a graduate student in Funari’s lab, the team prompted the loss of SMARCB1 in stem cells, then directed the cells to develop into neurons or into cerebral organoids – complexes of diverse nerve cells that mimic functional aspects of the developing brain in miniature.

In doing so, they identified a relationship between the loss of the gene and neural signals, which resulted in both a resistance to final neural development and a defect in maintaining normal cell health that showed similarity to patient tumors.

“With this new information in hand, our plan is to use our ATRT model and look for therapeutic targets that will cause these tumors to fully differentiate and therefore stop growing, which could prove to be an effective future therapy for ATRT,” Parisian said.

The journal Genes & Development published the study online.

– City News Service

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