Karin Forsberg Nilsson – Exploring brain tumour formation and invasion

Exploring novel regulators of tumour formation and targeting the invasive niche in brain tumours.

Glioblastoma is the most prevalent form of malignant primary brain cancer in adults. Despite therapeutic interventions such as surgical resection, irradiation, and chemotherapy, the median survival for GBM patients remains a mere 15 months. The aggressiveness of GBM is attributed to several factors, including its invasiveness, the presence of abundant and aberrant glioma-associated neovascularization, and the recruitment and accumulation of immune cells that foster an immunosuppressive tumour microenvironment.

Medulloblastoma is a predominantly pediatric brain tumour and it can to some extent be treated to meet the patient’s specific needs, but therapy for the most malignant forms is lacking. In addition, current treatment leads to long-term neurological and sensory consequences, further underscoring the need for improved diagnosis and treatment.

The overall goal of our research is to improve the treatment of malignant brain tumours, in particular glioblastoma (GBM) and medulloblastoma (MB). In our projects we incorporate our experience of neural stem cells with brain tumour biology, and cancer genomics, leveraging these fields to inform novel therapeutic possibilities.

Schematic drawing of different types of neural cells, dna, brain tumour cells and a brain, to illustrate how brain tumours arise through mutations in brain cells.

Brain tumours result from mutations in neural stem cells. Neural stem cells normally differentiate to mature cells types of the brain (neurons, astrocytes and oligodendrocytes). If mutations accumulate that lead to a dysregulated growth control, brain tumours may arise.

Leveraging non-coding mutations with evolutionary constraint to discover cancer driver genes in brain tumours

In this project, we explore non-coding mutations in brain tumours to decipher their function. Less than 1.5% of the human genome codes for proteins, and mutations in non-coding regulatory regions (~10%) have largely remained unexplored due to a lack of systematic approaches. We have developed a method to address this, hypothesizing that evolutionary conservation implies function. Leveraging non-coding mutations with scores for evolutionary constraint, we stratify functional mutations from passenger variants.

Schematic illustration of sequencing of brain tumours with drawings of a brain, a computer and a dna molecule.

Whole genome sequencing of malignant brain tumours. By sequencing a patient’s entire cancer genome, and comparing to DNA from normal cells of the same individual we can detect all mutations and decipher which ones are important for the disease. Graphic by L Gaffney.

By this new approach we identify and perform functional validation of non-coding mutations with regulatory potential in GBM and MB. We call these mutations non-coding constraint mutations (NCCMs).

In this project we combine whole genome sequencing of brain tumours, the HGCC glioblastoma stem cell repository (established as a collaboration between PIs in the NoDe research programme), and excellent biobanks U-CAN to map NCCMs in cancer of the brain.

Microscope images of cultured brain tumour cells stained in green and blue.

Examples of GBM cells from patients, grown under neural stem cell culture conditions. These cells retain important features of the patient’s tumour and are excellent models to study the disease. Phalloidin staining (green) depicts actin filaments and DAPI (blue) the cell nuclei. Photo: G Wicher.

Targeting the the extracelluar matrix in brain tumours for therapeutic intervention with focus on heparan sulfate proteoglycans

Any tumour stroma outside the brain is usually rich in fibrillar collagens, while in the brain, glycosaminoglycans, glycoproteins and proteoglycans are predominant constituents. Heparan sulfate proteoglycans (HSPGs) are composed of a core protein, to which highly charged, sulfated, disaccharide side chains are attached. The complexity of these side chains is the result of a series of enzymatic modifications that determine their capability to interact with e.g. growth factors. Therefore, remodelling of heparan sulfate (HS) and degradation of HS make up part of the malignant brain tumour signature.

We study HSPG biosynthesis and degradation in clinical brain tumour samples, cell cultures from GBM and medulloblastoma, as well as mouse models of these diseases. We have shown that chemical compounds that inhibit the enzyme heparanase reduces the growth of brain tumour cells. Results from this study are expected to validate and suggest new targets for brain tumour therapy. Possible routes for intervention could be aimed either at inhibiting tumour cell growth or invasiveness.

Drawings of the heparanase enzyme which degrades heparan sulfate proteoglycans, dividing cells that avoid cell death, cells that form blood vessels and a brain with invading tumour cells.

Role of HPSE in brain tumours. Overexpression of heparanase, the enzyme which degrades heparan sulfate proteoglycans, activates signalling pathways that are commonly associated with tumor growth and progression. Herpanase promotes brain tumour cell proliferation, suppresses cell death, stimulates tumour angiogenesis and cancer cell migration and invasion.

The influence of neuroinflammation on brain tumour growth

Knowledge about how the brain responds to a growing tumour remains limited. However, the tumour microenvironment plays a critical role in the progression of the disease. Brain tumours can be viewed as “wounds that can’t stop the healing process”. Drawing parallels between neuro-inflammation and cancer could shed light on the brain's transition to a milieu that fosters tumor growth.

Our research focuses on factors that regulate neuroinflammation in GBM, including the dynamics between tissue-resident cells and immune cells from the peripheral circulation. We examine the role of Interleukin-33 and its receptor, ST2, in shaping the inflammatory microenvironment within glioblastoma.

Microscope image of a mouse brain with a brain tumour with cells stained in different colours.

Mouse brain tumour with infiltrated immune cells Coronal section of a mouse brain with a tumour (glioma) in one of the hemispheres. Microglia and macrophages, two types of immune cells, are fluorescently labelled with CD11b in red, while the tumour cells (GL261) are marked with green fluorescent protein. Nuclei are stained with DAPI in blue, providing a comprehensive view of the tumour environment. Photo: G Wicher.