The cell of origin affects malignancy and drug sensitivity of brain tumours


Glioblastoma is the most common form of primary brain tumour in adults. Patients with glioblastoma have very poor prognosis since there are no effective therapies. In a new study researchers at IGP describe a correlation between the cell type from which the tumour originates and the growth and drug sensitivity of the tumour. More knowledge about the mechanisms behind this correlation could be important for developing more effective drugs against subgroups of glioblastoma.

The severe brain tumour type glioblastoma is essentially lethal. Presently, the development of more effective therapies is hampered by the large degree of tumour heterogeneity, both between different patients and in a single tumour. The heterogeneity between different tumours is partly due to that the tumour can originate from different kinds of brain cells. The tumour-originating cell can be either an immature neural stem cell or a more differentiated glial cell.

To develop improved therapies for glioblastoma, more knowledge is needed about how the cell of origin affects the characteristics of the cancer cells. Such studies must initially be performed in mice since it is not possible to charaterise the cell of origin in patient material. In the present study the researchers have used several clinically relevant glioblastoma models in mice and found that tumours that originated from immature neural stem cells developed faster than tumours that originated from more differentiated glial cells.

“We discovered that several important characteristics of the cancer cells could be linked to the tumour’s cell of origin. Immature neural stem cells gave rise to glioblastoma that grew faster and were more malignant than those that originated from glial cells. In tumours from neural stem cells there were also a more glioblastoma stem cells, cells that are believed to give cause to tumour recurrence after therapy,” says Lene Uhrbom, main responsible for the study.

To determine how the cell of origin affected the characteristics of glioblastoma cells, the researchers analysed how the activity for a large number of genes differed between tumours with different origins and they could identify a “gene signature” of almost 200 genes.

“When we compared the gene signature activity of glioblastoma cells from around 60 patients we found that a large number of patients could be divided into subgroups that showed a similar correlation between gene activity, tumour cell characteristics and cell of origin that we had seen in the mice study. This indicated that the cell of origin also has a direct influence on the characteristics of human tumours,” says Lene Uhrbom.

One feature of the tumour cells that the researchers were extra interested in was their sensitivity against cancer drugs and also in this case they found a correlation with the cell of origin. Glioblastoma cells from patients that through the gene signature analysis could be linked with an immature origin showed a generally higher sensitivity against cancer drugs than glioblastoma cells that were associated with a more differentiated cell of origin.

“We show that the cell of origin is important for the malignancy and drug sensitivity of glioblastoma cells, and that the findings also can be applied to glioblastoma cells from patients. We hope that the gene signature that we identified can form the basis for an improved classification of glioblastoma patients and for identifying new targets for therapy,” says Lene Uhrbom.

The study has been published in the journal Cell Reports and is a collaboration with researchers at Dept. of Medical Sciences, Dept. of Neuroscience and Dept. of Medical Biochemistry and Microbiology at Uppsala University, and the National Board of Forensic Medicine in Uppsala.

More information:
Paper in Cell Reports
Lene Uhrbom’s research