MYCN-induced molecular clock disruption and metabolic rewiring drive neuroblastoma
Neuroblastoma (NB) is one of the leading causes of pediatric cancer mortality. Despite advances in therapy, the survival rate for relapsed NB patients is dismal. MYCN is a major genetic driver for NB disease progression and relapse. However, targeting MYCN directly remains challenging, and novel therapeutic approaches against MYCN warrant in-depth investigations. Our lab has shown that MYCN profoundly rewires the way NB utilizes nutrients--specifically lipids--to drive oncogenesis. This function is effectively opposed by a core component of the circadian clock called BMAL1. BMAL1 is the central regulator of the molecular clock. Its expression and 24-hour-oscillation are rhythmically regulated by MYCN/REV-ERBa (which dampens BMAL1 expression) and RORa (which promotes BMAL1 expression) to keep cellular homeostasis. In NB, MYCN amplification represses BMAL1 expression and oscillation, disrupts metabolic homeostasis, and ultimately leads to dysregulated lipid metabolism and oncogenesis.
Project Goal:
We found that NB restoration of the molecular clock inhibits MYCN-driven lipid addiction and tumor growth. Additionally, BMAL1 genetic over-expression abrogates MYCN-driven rapid cell growth and lipogenic gene expression. We hypothesize that BMAL1 inhibits NB oncogenesis by opposing MYCN-induced lipid metabolism. This mechanism provides a unique therapeutic opportunity to control MYCN-driven tumor progression by restoring NB molecular clock and lipid metabolism. We will activate BMAL1 genetically to reverse MYCN-driven lipid addiction and tumor growth. We also propose that BMAL1’s ability to suppress lipid metabolism will create a time-specific window in which MYCN-amplified tumors are more vulnerable to metabolic inhibition. Overall, we aim to improve therapies for MYCN-amplified NB patients by characterizing how BMAL1 opposes MYCN in NB progression and metabolism, and exploiting novel time-specific metabolic interventions.
Project Update 2025:
Our ultimate goal is to provide a novel therapeutic strategy to treat MYCN amplified (MNA) high-risk neuroblastoma (NB) patients. We have shown that oncogenic MYCN directly changes the metabolism of neuroblastoma cells by upregulating all the steps of de novo lipogenesis (DNL). Newly synthesized lipids are essential for NB cells to grow and survive. We then found that ectopic restoration of BMAL1, the core component of the clock that keeps metabolic homeostasis, effectively blocks the synthesis, storage, and utilization of distinct lipids, resulting in a dramatic suppression of NB tumor growth. These findings support the hypothesis that the molecular clock could be employed to starve NB tumors from key nutrients and block their growth.
