Potential drug targets for glioblastoma identified in RNA-Seq data

rna-seq

Researchers at Karolinska Institutet have identified 10 tumour-specific potential drug targets for the brain tumour glioblastoma. The results are presented in the scientific journal Cell Reports.

“We have found disease-related changes in the cells that line the tumour blood vessels, so called endothelial cells, which have long been considered a possible clinical target for cancer treatment,” says Lynn Butler, assistant professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet, who led the study. “Proteins only expressed in the endothelial cells of the tumour vessels could be used as targets to attack the tumour’s blood supply, or for delivery of therapeutic agents, without affecting the normal brain.”

There are more than 200 different cell types in the human body, each performing their own role. Understanding the differences between these cell types helps us understand how organs work and how cells change in disease. Cell identity is determined by the specific proteins expressed, which can be predicted by measuring the protein transcripts found inside the cell. Changes in the endothelium of the cerebral vasculature can contribute to inflammatory, thrombotic, and malignant disorders. The importance of defining cell-type-specific genes and their modification in disease is increasingly recognized.

For this study, the researchers analysed human brain tissue and samples of the brain tumour glioblastoma, an incurable disease with a very high mortality rate. Existing data on transcripts from whole human brain tissue has limited usefulness when one is interested in the properties of a particular cell type, as these samples contain many different brain cell types. Now, the researchers have developed a new method to process this data and identify transcripts only expressed in certain types of brain cells. The researchers developed a bioinformatics-based approach to identify normal brain cell-enriched genes, using bulk RNA sequencing (RNA-seq) data from 238 normal human cortex samples from 2 independent cohorts. They compared endothelial cell-enriched gene profiles with astrocyte, oligodendrocyte, neuron, and microglial cell profiles. Endothelial changes in malignant disease are explored using RNA-seq data from 516 lower-grade gliomas and 401 glioblastomas. Lower-grade gliomas appear to be an “endothelial intermediate” between normal brain and glioblastoma.

The researchers apply their method for the prediction of glioblastoma-specific endothelial biomarkers, providing potential diagnostic or therapeutic targets.

“These markers could provide insights into the biology of glioblastoma and represent potential tumour-specific targets for therapy,” says Lynn Butler.

Source – Karolinska Institutet

Dusart P, Hallström BM, Renné T, Odeberg J, Uhlén M, Butler LM. (2019) A Systems-Based Map of Human Brain Cell-Type Enriched Genes and Malignancy-Associated Endothelial Changes. Cell Reports 29(6); 1690-1706. [article]

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