Turning the molecular clock back on suppresses neuroblastoma tumor
growth

Date:
July 27, 2021
Source:
Baylor College of Medicine
Summary:
Researchers show that restoring normal function of the molecular
clock suppresses tumor growth in advanced neuroblastoma and can
make tumors more sensitive to conventional chemotherapy.



FULL STORY ========================================================================== Researchers at Baylor College of Medicine and Texas Children's Cancer
Center have found that the molecular clock may be key to treating neuroblastoma. The researchers studied patients with high expression of
MYCN, known to be the major oncogenic driver of neuroblastoma. In those patients, two main components of the molecular clock were repressed
-- BMAL1, which oscillates to drive the clock cycle, and RORa, which
activates BMAL1. This repression correlated with poor clinical outcome.


==========================================================================
"We were very interested in how MYCN can reprogram tumor metabolism,"
said Dr.

Eveline Barbieri, assistant professor of pediatrics -- hematology
and oncology at Baylor. "We found that MYCN amplification inhibits
BMAL1 expression and oscillation, leading to metabolic reprograming
and oncogenesis." Because BMAL1 and RORa suppression allowed the
tumor cells to grow, the researchers wanted to know if restoring these components of the molecular clock would stop growth in neuroblastoma
cells. They tested two approaches in the lab -- genetic overexpression
of RORa and a pharmaceutical approach using a synthetic ligand that
reactivates RORa. Both techniques successfully restored BMAL1 expression
and oscillation.

Restoring the clock blocked tumor growth "Our strategy to restore BMAL1 expression also blocked tumor growth, suggesting that repression of
the molecular clock is indeed oncogenic," Barbieri said. "We believe restoration of the molecular clock is tumor suppressive in neuroblastoma."
The team's research also showed that restoring BMAL1 expression and
molecular clock function sensitized neuroblastoma tumors to conventional chemotherapy treatments, offering a potential future therapeutic approach.

"Our cells follow a molecular clock that controls cell metabolism,
much like the body's circadian rhythm controls sleep cycles.We know
metabolic processes are really important in how tumors develop
resistance to chemotherapy," Barbieri said. "In the future,
if we can develop therapeutics that restore the molecular
clock in a clinical setting, we may be able to use them in
combination with standard chemotherapy to avoid treatment resistance." ========================================================================== Story Source: Materials provided by Baylor_College_of_Medicine. Original written by Graciela Gutierrez. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Myrthala Moreno-Smith, Giorgio Milazzo, Ling Tao, Baharan Fekry,
Bokai
Zhu, Mahmoud A. Mohammad, Simone Di Giacomo, Roshan Borkar,
Karthik Reddy Kami Reddy, Mario Capasso, Sanjeev A. Vasudevan,
Pavel Sumazin, John Hicks, Nagireddy Putluri, Giovanni Perini,
Kristin Eckel-Mahan, Thomas P.

Burris, Eveline Barbieri. Restoration of the molecular clock is
tumor suppressive in neuroblastoma. Nature Communications, 2021;
12 (1) DOI: 10.1038/s41467-021-24196-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210727131440.htm

--- up 11 weeks, 4 days, 22 hours, 45 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)