How loss of single gene fuels deadly childhood brain cancer

September 10, 2020

Atypical teratoid rhabdoid tumors (ATRT) 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 and long-term survival is poor.

The cause of ATRT is primarily linked to inactivation of a gene called SMARCB1, part of a larger complex that helps regulate gene expression and developmental processes. In a study published online September 10, 2020 in the journal Genes & Development, an international team of scientists, led by researchers at 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 the gene negatively impacts neural development and promotes tumor 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, PhD, 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."

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

In doing so, they identified an interaction between the loss of SMARCB1 and neural differentiation pressure, which resulted in both a resistance to final differentiation and a defect in maintaining normal cell health that showed similarity to patient tumors.

"With this new information in hand," said 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."
-end-
Co-authors include: Tomoyuki Koga, Ludwig Institute for Cancer Research San Diego Branch and University of Minnesota; Shunichiro Miki, Ludwig Institute for Cancer Research San Diego Branch; Pascal D. Johann, Hopp Childrens Cancer Center, German Cancer Consortium and University Hospital Heidelberg; Marcel Kool, Hopp Childrens Cancer Center, German Cancer Consortium and Princess Maxima Center for Pediatric Oncology, the Netherlands; and John R. Crawford, UC San Diego.

University of California - San Diego

Related Brain Cancer Articles from Brightsurf:

Glioblastoma nanomedicine crosses into brain in mice, eradicates recurring brain cancer
A new synthetic protein nanoparticle capable of slipping past the nearly impermeable blood-brain barrier in mice could deliver cancer-killing drugs directly to malignant brain tumors, new research from the University of Michigan shows.

Cancer cells mediate immune suppression in the brain
Notre Dame researchers showed that one type of cell important for immunity, called a myeloid cell, can suppress the immune response -- which has the effect of allowing breast cancer cells to metastasize to the brain to form secondary tumor cells there.

New therapy targets breast cancer metastases in brain
When breast cancer spreads to the brain, the prognosis is grim.

AI may help brain cancer patients avoid biopsy
Brain cancer patients in the coming years may not need to go under the knife to help doctors determine the best treatment for their tumors.

Lung cancer therapy may improve outcomes of metastatic brain cancer
A medication commonly used to treat non-small cell lung cancer that has spread, or metastasized, may have benefits for patients with metastatic brain cancers, suggests a new review and analysis led by researchers at St.

Finding new clues to brain cancer treatment
Researchers at Case Western Reserve University School of Medicine and Cleveland Clinic new discovered a more accurate way to determine the relative life expectancy of glioblastoma victims and identify who could be candidates for experimental clinical drug trials by blending information from Artificial Intelligence (AI)--in this case, computer image analysis of the initial MRI scans taken of brain cancer patients--and genomic research.

Dynamic transition of the blood-brain barrier in the development of non-small cell lung cancer brain
Effective drug delivery through the BTB is one of the greatest therapeutic obstacles in treating brain metastases.

Blood test could help to accelerate brain cancer diagnosis
A blood test which could help to accelerate the diagnosis of brain cancer has been developed in research led at the University of Strathclyde.

The 'Goldilocks' principle for curing brain cancer
University of Minnesota Medical School researchers found that a stable body temperature holds the key to awakening the body's immune response to fight off brain cancer.

The path of breast-to-brain cancer metastasis
Scientists at EPFL's Swiss Institute for Experimental Cancer Research have discovered a signaling pathway that breast tumors exploit to metastasize to the brain.

Read More: Brain Cancer News and Brain Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.