Transcription factors regulate the expression of genes and control the development and function of all cells in the body. Researchers in the lab of Dr. Benjamin Deneen, associate professor of neuroscience and the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, found that transcription factor NFIA plays an important role in the development of astrocytes and oligodendrocytes cells that make up the support network in the brain. They then reasoned that changes in NFIA expression might lead these cell subpopulations to develop into certain types of glioma — a family of deadly brain tumors that arise from glial cells.
In a recent study published in Nature Neuroscience, researchers in Deneen’s lab found that both transcription factors NFIA and Sox10 play important roles in the development of different subtypes of glioma. While NFIA drives a stem cell to develop into an astrocyte, Sox10 plays a key role in the development of oligodendrocytes.
“Looking further into this developmental process, we found that Sox10 and NFIA work together in a checks and balance relationship,” said Deneen, who is senior author on the study. “We found that one works to antagonize the other’s function. NFIA inhibits Sox10’s activity in regulating oligodendrocyte differentiation, and conversely Sox10 antagonizes NFIA function and suppresses astrocyte differentiation,” thereby ensuring that an appropriate number of each cell type is generated during development.
Dr. Stacey Glasgow, postdoctoral fellow in neuroscience at Baylor and first author on the study, applied these findings to glioma subtypes in a recently developed mouse model where tumors with these specific glioma subtypes are developed in a matter of weeks as opposed to the months required with conventional mouse glioma models.
“Different subtypes of human glioma differentially express NFIA. Tumor expression patterns generally correlate with their normal/healthy lineage counterparts. In other words, astrocytes express high levels of NFIA while oligodendrocytes do not, and we observe these parallel relationships in human astrocytomas and oligodendrocytomas,” said Glasgow.
Glasgow and her colleagues were able to readily manipulate the expression of these transcription factors using their newly developed methods in the developing brain. Applying their new techniques, they overexpressed NFIA in oligodendrocytomas, which caused the existing gliomas to convert to an astrocytoma.
“We forced a tumor to express NFIA, converting the cell types from one type to another, thereby changing the tumor to a different sub-type of glioma,” Glasgow said. “We have shown that we can change tumor lineages, which opens the door for a new line of therapy and research focused on manipulating different glioma cell types to less malignant forms or forms that can be targeted with current treatments.”
In addition, these findings reveal a new logic to the broader convergence between development and cancer, where lineage specific developmental relationships oversee the generation of associated tumor sub-types. It may be that analogous relationships between sub-lineage developmental factors and tumor subtypes in other cancers also exist and may serve as a new approach towards differentiation therapies.
Additional co-authors on the study include Wenyi Zhu, Center for Cell and Gene Therapy at Baylor; Teng-Wei Huang and Jeffrey L. Neul, Baylor College of Medicine and the Dan L Duncan Neurological Research Institute at Texas Children’s Hospital; Carrie Mohila, Texas Children’s Hospital; C. Claus Stolt and Michael Wegner, Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen-Nürnberg; and Fuyi Chen and Joseph J. LoTurco, University of Connecticut.
Funding for this study was provided by the National Multiple Sclerosis Society (RG 4623A), the Sontag Foundation and the National Institutes of Health (R01 NS071153, R01 HD062553, R01HD055655, R01MH056524 and 5-T32HL092332-08).