Researchers at the Baylor College of Medicine and Texas Children's Cancer Center studied the positive effects in restoring RORa and BMAL1 activity and expression, discovering a new therapeutic approach to treating neuroblastoma. (Photo credit: BCM/Garciella Gutierrez)

Neuroblastoma (NB) is a type of cancer that arises from immature nerve cells present throughout the body. The cancer most often develops in and around the adrenal glands, which have nerve-like origins, lying above the kidneys. NB is the most prevalent cancer among infants (younger than 1 year old). 

Through the help of MYCN, neuroblastoma is able to adapt to its microenvironment much easier. MYCN (MYCN Proto-Oncogene, BHLH Transcription Factor) is a protein coding gene that is known to control rhythmic cell metabolism, which is intricately linked to circadian rhythm. Mechanistically, the protein coding gene suppresses BMAL1 production and oscillation, improving cell survival by negatively regulating the molecular clock.

Due to MYCN's role as a regulator of metabolic reprogramming, increased amounts of MYCN disrupts molecular clock loops and suppresses the role of BMAL1. The BMAL1 protein is an important component of the transcription-translation negative feedback loop (TTFL), which is responsible for the generation of molecular circadian rhythms. According to research, BMAL1 is the only clock gene that is essential for the circadian clock to work in humans.

In a recently published study, researchers at Baylor College of Medicine and Texas Children's Cancer Center focused on whether restoring BMAL1, through the activation of RORa, would help cease the growth of neuroblastoma cells. 

The researchers found that stimulating the activator, RORa, increased BMAL1 activity and suppressed MYCN. The expression was found to sensitize neuroblastoma tumors to conventional chemotherapy. The study resulted in a suppression of tumor growth as well as a new therapeutic method against neuroblastoma by blocking the dysregulation of these cells. 

Dr. Eveline Barbieri, specialized in pediatric oncology and one of the paper's authors stated, "Our strategy to restore BMAL1 expression also blocked tumor growth, suggesting that repression of the molecular clock is indeed oncogenic. We believe restoration of the molecular clock is tumor suppressive in neuroblastoma."

The NB cells were maintained and grown in a high glucose medium. Amounts of BMAL1 and RORa were monitored and tampered. Tumor weights were then measured and compared to each other. 

The results highlight the importance of BMAL1 and RORa in suppressing neuroblastoma growth. The findings allow for potential new and therapeutic ways of approaching tumors and chemotherapy treatments. 

"Our cells follow a molecular clock that controls cell metabolism, much like the body's circadian rhythm controls sleep cycles," Dr. Barbieri added. "We know metabolic processes are really important in how tumors develop resistance to chemotherapy. 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."

The study was published in Nature Communications, on June 28th, 2021.

Abstract. MYCN activation is a hallmark of advanced neuroblastoma (NB) and a known master regulator of metabolic reprogramming, favoring NB adaptation to its microenvironment. We found that the expression of the main regulators of the molecular clock loops is profoundly disrupted in MYCN-amplified NB patients, and this disruption independently predicts poor clinical outcome. MYCN induces the expression of clock repressors and downregulates the one of clock activators by directly binding to their promoters. Ultimately, MYCN attenuates the molecular clock by suppressing BMAL1 expression and oscillation, thereby promoting cell survival. Reestablishment of the activity of the clock activator RORĪ± via its genetic overexpression and its stimulation through the agonist SR1078, restores BMAL1 expression and oscillation, effectively blocks MYCN-mediated tumor growth and de novo lipogenesis, and sensitizes NB tumors to conventional chemotherapy. In conclusion, reactivation of RORĪ± could serve as a therapeutic strategy for MYCN-amplified NBs by blocking the dysregulation of molecular clock and cell metabolism mediated by MYCN.

Moreno-Smith, M., Milazzo, G., Tao, L. et al. Restoration of the molecular clock is tumor suppressive in neuroblastoma. Nat Commun 12, 4006 (2021). https://doi.org/10.1038/s41467-021-24196-4

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