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 the human brain.
The study, published in Cancer Cell, reveals that a third of the cells in glioma, a type of brain tumor, fire electrical impulses. These impulses, also called action potentials, originate from tumor cells that are part neuron and part glia. This finding supports the groundbreaking idea that neurons are not the only cells capable of generating electric signals in the brain. The scientists also discovered that cells with hybrid neuron-glia characteristics are present in the non-tumor human brain. The findings highlight the importance of further studying these newly identified cells' roles in both glioma and normal brain function.
“Gliomas are the most common tumors of the central nervous system with an estimated 12,000 cases diagnosed each year. These tumors are universally lethal and have devastating effects on neurological and cognitive functions. Previous studies have shown that patient survival outcomes are associated with tumor proliferation and invasiveness, which are influenced by tumor intrinsic and extrinsic factors, including communication between tumor cells and neurons that reside in the brain,” said 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, a member of the Dan L Duncan Comprehensive Cancer Center at Baylor and a principal investigator at the Jan and Dan Duncan Neurological Research Institute.
Researchers have previously described how glioma and surrounding healthy neurons connect with each other and how neurons communicate with tumors to drive growth and invasiveness.
“We have known for some time now that tumor cells and neurons interact directly,” said first author Dr. Rachel N. Curry, postdoctoral fellow in pediatrics – neuro-oncology at Baylor, who was responsible for conceptualizing 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 to ensure cell biology was preserved as much as possible.”
To study glioma cells' ability to spike electrical signals and identify which cells produce them, researchers used Patch-sequencing—a combination of techniques integrating whole-cell electrophysiological recordings to measure spiking signals with single-cell RNA-sequencing—and analysis of cellular structure to identify cell types.
The electrophysiology experiments were conducted by research associate Dr. Qianqian Ma in co-corresponding author associate professor Dr. Xiaolong Jiang's lab within Baylor's neuroscience department.
“We were truly surprised to find these tumor cells had a unique combination of morphological and electrophysiological properties,” Ma said.
“We conducted all these analyses on single cells," Deneen added."We analyzed their individual electrophysiological activity; we extracted each cell’s content; sequenced RNA to identify active genes; stained each cell with dyes visualizing structural features.”
Integrating this vast amount of data required developing novel analytical methods.
“To define spiking cells' identity," explained co-corresponding author Dr. Akdes Serin Harmanci,"we developed Single Cell Rule Association Mining (SCRAM) to annotate each cell individually."
“Finding so many glioma cells electrically active was surprising because it challenges long-held neuroscience concepts stating only neurons fire electric impulses,” Curry noted.“Our findings show human non-neuronal cells can fire electrical impulses.”
“Moreover," Harmanci added,"comprehensive data analyses revealed spiking hybrid glioma tumors had both neuronal/OPC properties.” Non-tumor neuron-glia hybrids suggest this population contributes not only to glioma growth but also healthy brain function."
“The proportion of spiking hybrid glioma may have prognostic value,” concluded co-corresponding author Dr.Ganesh Rao.“More spiking hybrid gliomas correlate better survival outcomes—valuable information for patients/doctors.”
“This work resulted from extensive interdisciplinary collaboration across neurosurgery,bioinformatics,cancer modeling—strongly supported by state-of-the-art groups at Baylor,”Deneen said.“Results offer enhanced understanding/gliomas/normal brain function,sophisticated bioinformatics pipeline/potential prognostic implications/devastating disease.”
Other contributors include Malcolm F.McDonald,Yejung Ko,Srignha Srivastava,Pey-Shyuan Chin,Pheihao He,Brittney Lozzi,Prazwal Athukuri,Junszhan Jing,Sue Wang,Ari O.Harmanci,Benjamen Arenkiel.Affiliations:Baylor College Medicine,Duncan Neurological Research Institute/Texas Children’s Hospital/University Texas Health Science Center,Houston
This work supported by NIH grants (R35-NS132230,R01NS124093,R01CA223388,U01CA281902,R01NS094615,T32HL92332,F31CA265156,F99CA274700).Further support:NIH Shared Instrument Grants(S10OD023469,S10OD025240,P30EY002520),CPRIT grant RP200504.David/Eula Wintermann Foundation
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