Researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital have uncovered a new cell type in human brain cancers. Their study, published in Cancer Cell, reveals that a third of the cells in glioma, fire electrical impulses. Interestingly, the impulses, also called action potentials, originate from tumour cells that are part neuron and part glia, supporting the groundbreaking idea that neurons are not the only cells that can generate electric signals in the brain.
The scientists also discovered that cells with hybrid neuron-glia characteristics are present in the non-tumour human brain. The findings highlight the importance of further studying the role of these newly identified cells in both glioma and normal brain function.
“Previous studies have shown that patient survival outcomes are associated with tumour proliferation and invasiveness, which are influenced by tumour intrinsic and extrinsic factors, including communication between tumour cells and neurons that reside in the brain,” said Dr Benjamin Deneen, professor in the Department of Neurosurgery at Baylor.
Researchers have previously described that glioma and surrounding healthy neurons connect with each other and that neurons communicate with tumours in ways that drive tumour growth and invasiveness.
“We have known for some time now that tumour cells and neurons interact directly,” said first author Dr Rachel N. Curry, postdoctoral fellow in paediatrics – neuro oncology at Baylor, who was responsible for conceptualising the project. “But one question that always lingered in my mind was, ‘Are cancer cells electrically active?’ To answer this question correctly, we required human samples directly from the operating room. This ensured the biology of the cells as they would exist in the brain was preserved as much as possible.”
To study the ability of glioma cells to spike electrical signals and identify the cells that produce the signals, the team used Patch-sequencing, a combination of techniques that integrates whole-cell electrophysiological recordings to measure spiking signals with single-cell RNA-sequencing and analysis of the cellular structure to identify the type of cells.
The electrophysiology experiments were conducted by research associate and co-first author Dr Qianqian Ma in the lab of co-corresponding author associate professor of neuroscience Dr Xiaolong Jiang. This innovative approach has not been used before to study human brain tumour cells. “We were truly surprised to find these tumour cells had a unique combination of morphological and electrophysiological properties,” Ma said. “We had never seen anything like this in the mammalian brain before.”
“We conducted all these analyses on single cells. We analysed their individual electrophysiological activity. We extracted each cell’s content and sequenced the RNA to identify the genes that were active in the cell, which tells us what type of cell it is,” Deneen said. “We also stained each cell with dyes that would visualise its structural features.”
Integrating this vast amount of individual data required the researchers to develop a novel way to analyse it.
“To define the spiking cells and determine their identity, we developed a computational tool – Single Cell Rule Association Mining (SCRAM) – to annotate each cell individually,” said co-corresponding author, Dr Akdes Serin Harmanci, assistant professor of neurosurgery at Baylor.
“Finding that so many glioma cells are electrically active was a surprise because it goes against a strongly held concept in neuroscience that states that, of all the different types of cells in the brain, neurons are the only ones that fire electric impulses,” Curry said. “Others have proposed that some glia cells known as oligodendrocyte precursor cells (OPCs) may fire electrical impulses in the rodent brain, but confirming this in humans had proven a difficult task. Our findings show that human cells other than neurons can fire electrical impulses. Since there is an estimated 100 million of these OPCs in the adult brain, the electrical contributions of these cells should be further studied.”
“Moreover, the comprehensive data analyses revealed that the spiking hybrid cells in glioma tumours had properties of both neurons and OPC cells,” Harmanci said. “Interestingly, we found non-tumour cells that are neuron-glia hybrids, suggesting that this hybrid population not only plays a role in glioma growth but also contributes to healthy brain function.”
“The findings also suggest that the proportion of spiking hybrid cells in glioma may have a prognostic value,” said co-corresponding author Dr Ganesh Rao, professor and chair of neurosurgery at Baylor. “The data shows that the more of these spiking hybrid glioma cells a patient has, the better the survival outcome. This information is of great value to patients and their doctors.”
“This work is the result of extensive equal collaboration across multiple disciplines – neurosurgery, bioinformatics, neuroscience and cancer modelling – disciplines strongly supported by state-of-the-art groups at Baylor,” Deneen said. “The results offer an enhanced understanding of glioma tumours and normal brain function, a sophisticated bioinformatics pipeline to analyse complex cellular populations and potential prognostic implications for patients with this devastating disease.”
Source: Baylor College of Medicine
