Memphis, Tennessee – MYCN is a gene associated with cell proliferation and growth, which is mutated in many types of cancer. Scientists at St. Jude Children’s Research Hospital studying high-risk neuroblastoma found that MYCN plays a role in modifying the cellular state, causing a positive feedback loop that leads to a faster progressing disease. Their work to understand this process revealed a potential therapeutic target in the protein KDM4. Inhibiting KDM4 demonstrated strong anticancer activity by blocking MYCN expression. The work was published today in Cell Reports Medicine.
Neuroblastoma is a cancer that develops in immature nerve cells and can affect different parts of the body. It most commonly occurs in children under the age of five years old. Cells within neuroblastoma’s tumor microenvironment have different states or personalities. These states are classified as either slow-dividing mesenchymal, a methodical and deliberate personality, or rapidly dividing adrenergic, an energetic personality. Cells are classified primarily based on their gene signatures, akin to a personality test. However, cells can change their personalities, transitioning from mesenchymal to adrenergic.
The St. Jude team showed that the MYCN protein promotes a cellular state switch in the MYCN-amplified neuroblastoma microenvironment. This leads to a change in primitive mesenchymal cells, where they adopt an adrenergic state. This switch, in turn, reinforces the regulation of MYCN expression through KDM4, regulates core transcription factors and maintains the cells in the adrenergic state, leading to a more aggressive cancer.
MYCN-driven personality change drives tumor growth
The high risk associated with MYCN-amplified neuroblastoma stems from its clinical heterogeneity. The St. Jude team explored the transcriptional profiles of the different cell states within neuroblastoma, hoping to identify a route for more targeted, less intensive therapies. Currently, treatment for neuroblastoma is taxing, involving chemotherapy, radiation, immunotherapy and stem cell transplantation, underscoring the need for novel treatment options.
The researchers found that the high levels of MYCN were a driving force behind the observed cellular personality switch from mesenchymal to adrenergic cells. “We used neural cell lines that were largely mesenchymal,” said Jun Yang, MD, PhD, St. Jude Department of Surgery. “When we added MYCN to these cells, they changed their genetic signature from mesenchymal to adrenergic.”
Yang was examining the genetic signature of the transcription factors comprising the core regulatory circuitry (CRC TFs), which function as master controllers of cellular identity through genetic regulation.
The researchers found that MYCN was responsible for inducing adrenergic-associated CRC TFs — essentially reprogramming the cell’s personality. This change also accompanied the induction of another protein, KDM4, which has its own role in gene regulation.
“When MYCN caused the cells to change, we found KDM4 expression was up when MYCN was high. That made us hypothesize that maybe KDM4 is important to help MYCN maintain the adrenergic state or help it work from the mesenchymal to adrenergic state,” said Yang.
KDM4 opens therapeutic window
While MYCN induces KDM4 expression, KDM4 helps maintain the adrenergic cell state through subsequent regulation of MYCN expression in a positive feedback loop. Confirming the link between MYCN and KDM4 opened a window of opportunity for the researchers.
“Since MYCN-amplified tumors are high-risk, we thought maybe if we treat this tumor with a KDM4 inhibitor, we could delay the tumor growth or have an anti-cancer effect,” said Yang.
The addition of the KDM4 inhibitor QC6352 to adrenergic cells with a MYCN amplification repressed key neuroblastoma oncogenes, including MYCN and adrenergic CRC TFs. The drug demonstrated significant antitumor qualities in disease models through the downregulation of chromatin accessibility at MYCN’s gene location. The ubiquitous nature of MYCN induction in neuroblastoma cases implies that targeting its role in maintaining an adrenergic state is a promising route for future therapeutic design.
When mouse models were treated with the KDM4 inhibitor combined with chemotherapy, the chemotherapy-resistant MYCN-amplified tumors showed complete responses. “This indicated to us that targeting KDM4 could significantly improve the efficacy of the standard of care patients receive,” concluded Yang.
Authors and funding
The study’s first authors are Ahmed Abu-Zaid, Jie Fang, Hongjian Jin and Shivendra Singh of St. Jude. The study’s other authors are Prahalathan Pichavaram, Qiong Wu, Heather Tillman, Laura Janke, Wojciech Rosikiewicz, Beisi Xu, Lee-Ann Van De Velde, Yian Guo, Yimei Li, Noha Shendy, Ian Delahunty, Zoran Rankovic, Taosheng Chen, Xiang Chen, Mark Hatley, Adam Durbin, Andrew Murphy, Paul Thomas and Andrew Davidoff of St. Jude; Kevin Freeman, of The University of Tennessee Health Science Center; and Peter Murray, of Max Planck Institute of Biochemistry.
The study was supported by grants from the American Cancer Society (130421-RSG-17-071-01-TBG), the National Cancer Institute (1R01CA229739-01, 1R01CA266600-01A1) and ALSAC, the fundraising and awareness organization of St. Jude.
About St. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children.
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