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. When we added MYCN to these cells, they changed their genetic signature from mesenchymal to adrenergic.
Jun Yang, MD, PhD, St. Jude Department of Surgery
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.
Jun Yang, MD, PhD, St. Jude Department of Surgery
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.
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.
(Newswise/NJ)
