Bengt Westermark – Human malignant glioma – from oncogenic mechanisms to treatment

Our research is focused on glioblastoma, which is the most common malignant adult brain tumor. The knowledge about molecular mechanisms involved in glioblastoma development has increased dramatically during the last decades. Despite this progress, the prognosis for glioblastoma patients remains poor, and new treatment modalities are needed in order to improve patient outcomes.

We study human glioma cells in culture, derived from fresh tumor tissue resected during brain tumor surgery. These cells serve as a tool to test different hypotheses in a controlled setting. The research centers around a growth factor (BMP4), a cell cycle inhibitor (p21), and a transcription factor (SOX2), crucial regulators in glioblastoma biology governing stemness, differentiation, and growth control.

The role of SOX2

Project 1 focuses on developing a controllable system enabling studies of the role in SOX2 in glioblastoma. We analyze the effects of SOX2 gene knock-out on glioblastoma cell proliferation, gene expression, and tumor formation upon orthotopic transplantation in immune deficient mice. We also aim to develop efficacious SOX2 inhibitors in a drug development program. Preliminary findings suggest reduced tumorigenic potential in SOX2 knockout cells, indicating promising therapeutic avenues.

Regulation of cell size

Project 2 investigates cell size regulation in glioblastoma. Exposure of glioblastoma cells to BMP4 leads to an increase in cell size, mediated by p21. Mechanisms regulating the coordination between the cell cycle and cell growth have only been partially elucidated. We focus on identifying genes associated with cell size variation in glioblastoma cells. We leverage proteome data and conduct targeted CRISPR screens to identify candidate genes involved in cell size regulation.

Change in cell states

In project 3, we study single-cell-derived cultures (clones) from the same glioblastoma tumor sample (Segerman et al., Cell Reports, 2016). We find that the cancer cells naturally, but at low speed, can slide back and forth between more treatment-resistant (mesenchymal-like) and more treatment-sensitive (proneural-like) cell states. The project aims to identify regulatory mechanisms behind this spontaneous change in cell state and based on this knowledge find drugs/substances or combinations of these that induce the cell state linked to treatment sensitivity.

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