Ependymoma Cancer Malignancy - Role of Serotonin-Producing Neurons

In ependymoma patients, communication between tumor cells and serotonin-producing neurons drives tumor malignancy, study leads the way to new therapies.

The significance of tumor-neuron interactions in controlling the progression of ependymoma brain tumors has been discussed in a study. The link between neuronal signaling and alterations in DNA-binding proteins in promoting malignancy in brain cancer has been emphasized. This investigation was conducted by scientists at Baylor College of Medicine and St. Jude Children’s Research Hospital and published in Nature ().

“Ependymomas are the third most common type of pediatric brain tumors,” said co-corresponding author, Dr. Benjamin Deneen professor and Dr. Russell J. and Marian K. Blattner Chair in the Department of Neurosurgery, director of the Center for Cancer Neuroscience and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “These tumors are aggressive, resistant to chemotherapy, and lack tumor-specific therapies, leading to poor survival.”

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Ependymoma, the rare form of brain cancer that occurs in children, can be diagnosed used a marker called TPR gene.

‘Did You Know?
Ependymoma is a primary tumor that occurs in the brain or spinal cord. Typically, these tumors do not spread beyond the brain or spinal cord. They can develop in both adults and children; however, they are more prevalent in children. #ependymoma #braincancer #medindia’

Purpose of Study: New Treatment Therapy and Patient Survival

“We have not made an impact on patient survival in the last three decades. A major factor has been a poor understanding of the disease. The motivation of our collaborative work with the Deneen lab is to dissect the biology of these tumors as a basis for developing new therapies,” said co-corresponding author Dr. Stephen Mack, associate member at St. Jude Children’s Research Hospital and member of the Department of Neurobiology, Neurobiology and Brain Tumor Program and Center of Excellence in Neuro-Oncology Sciences.

Research conducted in the past on other types of brain tumors has indicated that the brain activity surrounding a brain tumor can impact its growth.

“In the current study, we investigated whether brain activity played a role in ependymoma growth, specifically in a very aggressive type driven by a protein called ZFTA-RELA,” said first author Hsiao-Chi Chen, a graduate student in the Deneen lab. “In collaboration with the Mack lab, we developed an animal model to study this rare pediatric brain tumor and validated these findings in human tumor samples.”

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New Events Affecting Tumor Growth Discovered

Scientists discovered unusual neuronal behavior around ependymomas and investigated its impact on tumor growth. They found that while heightened activity in some neural pathways promoted tumor development, increased activity in others surprisingly inhibited it—an undocumented phenomenon. This research reveals a new sequence of events affecting tumor growth, potentially opening avenues for therapeutic interventions.

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Effect of Serotonin on Expression of Genes

“First, we found that normal neurons located in the brain region called dorsal raphe nucleus (dRN) project towards the cortex, where ependymoma grows. These neurons secrete serotonin, a brain chemical that carries messages between nerve cells, which surprisingly slows tumor growth,” Chen said.

Interestingly, ependymoma cells carry a serotonin transporter, a molecule that imports serotonin within the cell. “We were surprised to discover that serotonin enters ependymoma cells and binds to histone H3, a protein that is tightly associated with DNA,” Chen said. “Histone serotonylation, the addition of serotonin to histone, regulated tumor growth. Promoting it enhanced tumor growth while preventing it slowed down ependymoma growth in animal models.”

“Discovering histone serotonylation in ependymoma piqued our interest because a previous study from our lab had revealed that adding serotonin to histones affects which genes the cell turns on,” Deneen said.

The research team found that histone serotonylation in ependymoma intensifies the expression of transcription factors, which are genes responsible for regulating the expression of other genes. Chen said, “We focused on transcription factor ETV5 whose overexpression accelerated tumor growth. But how does it do it?”

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Surrounding Environment Affects Tumor Progression- Avenue for Potential Therapies

Subsequent trials showed that ETV5 expression causes changes in chromatin structure, the complex of DNA, and proteins present in chromosomes. These changes inhibit the activation of neurotransmitter genes. Specifically, low levels of neuropeptide Y (NPY) in tumors contributed to tumor growth and neural activity. Increasing the levels of NPY in tumors slowed tumor progression by remodeling the surrounding synapses or communication between neurons.

“We knew that brain tumors release factors that remodel synapses towards hyperactivity. Here we found the opposite also can happen, that ependymoma tumors can release factors that suppress excitatory synaptic remodeling and that repressing this mechanism is essential for tumor progression,” Deneen said.

“I am excited that this work has redefined our understanding of how brain tumor cells grow, and how they take advantage of factors in their surrounding environment to initiate tumors,” Mack said. “I am equally excited that this work has revealed many new avenues for research that may in the future lead to new therapies, which is desperately needed for this devastating disease.”

Reference:

Histone serotonylation regulates ependymoma tumorigenesis - (https://www.nature.com/articles/s41586-024-07751-z)

Source-Medindia