How loss of single gene fuels deadly childhood brain cancer
Using stem cells, researchers describe how developing neurons are blocked
and tumors started

Date:
September 10, 2020
Source:
University of California - San Diego
Summary:
Researchers describe how the functional loss of a single gene
negatively impacts neural development and promotes the growth of
a particularly deadly form of pediatric brain cancer.



FULL STORY ========================================================================== 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."

========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Scott
LaFee. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Alison D. Parisian, Tomoyuki Koga, Shunichiro Miki, Pascal
D. Johann,
Marcel Kool, John R. Crawford, Frank B. Furnari. SMARCB1 loss
interacts with neuronal differentiation state to block maturation
and impact cell stability. Genes & Development, 2020; DOI:
10.1101/gad.339978.120 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200910150241.htm

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