Researchers at Uppsala University have detected different subgroups of the brain tumour form glioblastoma, where the cancer cells’ properties depend on which cell type they originate from. The used analysis method could also separate glioblastoma patients with significant differences in survival. The findings open up for identifying specific therapeutic targets for the new subgroups of glioblastoma.

Experimental study/Cells

Glioblastoma is the most frequent and most lethal primary malignant brain tumour, with more than 300 cases per year in Sweden. Despite intensive therapy with surgical resection, radiotherapy and chemotherapy, most patients die within one year after diagnosis due to disease relapse. There is a lot of information available about the genetics behind glioblastoma but this has so far not resulted in any therapeutic breakthroughs and only a few markers for disease prognosis.

In a study published in the journal Nature Communications, three research teams have worked in close collaboration and analysed glioblastoma cells from 58 patients. They used a sequencing technology that generates global information about of the cancer cells’ epigenetics, i.e. changes in the genome that are not caused by direct mutations.

“The work is based on our previous studies where we show that different glioblastoma progenitor cells have a great impact on tumour development and important properties of the cancer cells. Since epigenetic analysis is a very sensitive method for distinguishing normal cell types, we hoped that it would also provide new knowledge about developmental biological mechanisms in glioblastoma,” says Lene Uhrbom at the Department of Immunology, Genetics and Pathology, who led the study together with Xinqi Chen at the same department.

The researchers used the unique, local biobank HGCC (Human Glioblastoma Cell Culture), which consists of glioblastoma cells from patients, and analysed samples from the biobank with a new sequencing technology called ATAC-seq. By separating the patients based on the epigenetic information of their glioblastoma cells, they were able to identify three groups in which also central functional properties of the cancer cells, such as cell division, invasiveness and treatment resistance, were found to be distinct.

Two of the groups also showed a significant difference in patient survival. This has not been shown in previous molecular analyses because the two groups are very similar and have belonged to the same genetic subgroup.

“To understand the background for the epigenetic groups of glioblastoma, we compared the patient data with the same type of epigenetic analysis of glioblastoma cells from mouse models, where the tumours originated from three different normal cell types in the brain. We found a link between the different cells of origin in mice and the three patient groups of glioblastoma. This strengthens the relationship between developmental biological origin and the properties of tumour cells, says Xingqi Chen.

The findings may lead to refined prognostic tools and open up for the development of targeted therapy for defined subgroups of glioblastoma patients.

Lu, X., Maturi, N.P., Jarvius, M. et al. Cell-lineage controlled epigenetic regulation in glioblastoma stem cells determines functionally distinct subgroups and predicts patient survival. Nat Commun 13, 2236 (2022), DOI: 10.1038/s41467-022-29912-2, https://www.nature.com/articles/s41467-022-29912-2#citeas

Further information:

Lene Uhrbom, Senior Lecturer/Associate Professor at Department of Immunology, Genetics and Pathology, Uppsala University, lene.uhrbom@igp.uu.se, +46 18-471 50 63

Xingqi Chen, Associate senior lecturer/Assistant Professor at Department of Immunology, Genetics and Pathology, Uppsala University, xingqi.chen@igp.uu.se, +46 18-471 40 72

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