Loss Of Gene Fuels Childhood Brain Cancer

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Atypical teratoid rhabdoid tumours are a rare but fasting growing form of brain cancer that typically affects children who are three years of age or younger but can occur in older children and adults. Long term survival is poor with ATRT, and there are a variety of treatments there is no definitive standard of care. 

The cause of atypical teratoid rhabdoid tumours is linked to the inactivation of the SMARCB1 gene, which is part of a larger complex that helps to regulate gene expression and developmental processes. This study published in the journal Genes & Developments using stem cells describes how the loss of the single gene can negatively impact neural developments and promote tumour growth. 

“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, Ph.D., professor of pathology and Ludwig San Diego member.

“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.

The loss of SMARCB1 was prompted in human-induced pluripotent stem cells, the team directed the iPSCs to develop into neurons or into cerebral organoids which are complexes of diverse nerve cells and glia that mimic functional aspects of the developing brain in miniature; in doing so an interaction was identified between the loss of SMARCB1 and neural differentiation pressure which resulted in a resistance to final differentiation and a defect in maintaining normal cell health that showed similarity to patient tumours. 

“With this new information in hand,” said Alison D. Parisian, “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.”



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