Fredrik Swartling – Mechanisms behind childhood brain tumours

In our research we study how childhood brain cancers develop and whether we can find new treatments for these tumours. Using advanced modelling systems and single-cell analysis, we study genetic changes and proteins that are dysregulated in brain tumours. We are also trying to understand why some tumours relapse and how this can be treated.

MYC proteins (like MYC or MYCN) are transcription factors and PDGF proteins and their receptors are growth factors which all have essential roles in normal brain development. Misexpression of MYC proteins occurs frequently in medulloblastoma, the most common malignant childhood brain tumour of the hindbrain and PDGF and its receptors when mutated or amplified, promote the growth of malignant gliomas.

MYC or MYCN amplifications in medulloblastoma are strongly correlated with poor prognosis, suggesting that MYC proteins are clinically relevant targets for brain tumour therapy. MYC and PDGF proteins are also amplified or overexpressed in diffuse midline gliomas of in the childhood brain stem and in certain subtypes of glioblastoma, high grade malignant brain tumours typically occurring in the forebrain of adults.

We use various models to mimic the tumors caused by these proteins and study tumor cells grown in so-called stem cell cultures or as 3D cultures, known as organoids. We aim to identify which cells in the brain can serve as cells of origin for brain tumors and therefore compare these cell types with samples and cells from brain tumor patients. We model how different regions of the brain develop in organoids, such as the brainstem, cerebellum, and cerebrum.

Tumour origin and therapy resistance

Our research group explores how MYC proteins generate malignant brain tumours with a focus on identifying cells of tumour origin. We study critical pathways involved in relapse driven by another protein SOX9 that is important for stem cell features but also in promoting therapy resistance.

We have generated clinically relevant molecularly defined models for MYC/MYCN-driven brain tumours and we also study a large number of primary cell lines obtained from childhood brain tumour patients. Finally, we are developing forward genetic screens, clonal cell analysis, drug screening and novel computational models to understand the genomics, transcriptomics and epigenetics of these tumours at the single cell level.

Read more about our research

Microscope image showing the clear structure of a normal cerebellum compared to the disorganised medulloblastoma structure.

Normal cerebellar structure (left) as compared to the disorganised medulloblastoma structure (right)

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