Neural Stem Cells and Brain Tumors

The overall goal of our research is an improved treatment of malignant brain tumours, in particular glioblastoma and medulloblastoma. In our projects we incorporate experience of neural stem cells with glioma biology, leveraging the close relationship between these two fields. We also investigate the neuro-inflammatory responses to brain tumours and traumatic brain injury.

Specific goals are:

  1. To target the invasive niche of brain tumours with novel experimental therapies (KFN).
  2. To establish reliable in vitro tumour models and employ these to explore novel regulators of tumour formation (KFN).


Extracellular matrix interactions of importance for brain tumour formation and neural development

Argyris Spyrou, Lulu Rama Haseeb, Grzegorz Wicher, Karl Holmberg Olausson, Anqi Xiong

The focus of this project is the “brain tumour niche” that allows tumour cells to detach from the original site, remodel the extracellular matrix (ECM) and migrate to seed new tumours that ultimately leads to death of the patient. Based on our increased understanding of the biochemical and molecular determinants of brain tumour invasion, new drug targets in the glioma microenvironment could be identified.

Heparan sulfate (HS) proteoglycans are main components of the ECM where they interact with a large number of physiologically important macromolecules, thereby influencing biological processes. HS modulates growth factor activities, and we have shown a vital role for HS in formation of the neural lineage. The major enzymatic activity degrading HS is heparanse.

In this project we address HS proteoglycan biosynthesis and degradation in clinical brain tumour samples, human glioma and medulloblastoma cell culture as well as mouse and human models of glioma and medulloblastoma (Kundu et al, 2016, Xiong et al, 2017, Spyrou et al, 2017).
 

Human glioma cell cultures as a new experimental platform

Grzegorz Wicher, Argyris Spyrou, Karl Holmberg Olausson, Lulu Rama Haseeb

Basic cancer research, including preclinical tumour models and testing of candidate drugs needs optimized in vitro models that better reflect the patient’s disease. There are major challenges in generating model systems at the scale necessary to demonstrate patient tumour heterogeneity.

The availability of “tumour stem cell” culture techniques has opened the possibility to create well-characterized human tumour cell cultures. However, to establish these experimental tools requires simultaneous access to the technical know-how of culturing and analysing cancer cells, and a systematic biobanking pipeline of patient tissue combined with clinical data acquisition.

All these parameters are now in place at the Rudbeck Laboratory through a collaborative effort (www.hgcc.se) between K. Forsberg Nilsson, L. Uhrbom, B. Westermark, and S. Nelander, clinical collaborators G. Hesselager and I. Alafuzoff, Uppsala University Hospital and the U-CAN project (www.u-can.uu.se).
 

Investigating regulators for brain tumours and neural stem cells

Anqi Xiong, Karl Holmberg Olausson

We previously reported that malignant brain tumours and neural stem cells share a common transcriptional signature (Demoulin et al, 2006) and selected the pseudokinase nuclear receptor binding protein 2 (NRBP2), for further study because of the high level of regulation (Larsson et al, 2008).

Pseudokinases have high sequence similarity to mechanistically validated enzymes, but are devoid of the catalytic activity (NRBP2 lacks 7 out of 15 residues of the kinase domain) and are now increasingly viewed as components of signalling pathways. We are now working to identify the function of NRBP2 and its role in brain tumour development.

Dogs provide valuable spontaneous models for complex human diseases and certain dog breeds exhibit a considerably elevated risk of developing glioma. We have identified a genomic region associated strongly with glioma in dogs (Truvé et al, 2016) and will explore candidate genes, expressed differentially in glioma and the healthy brain, for their roles in tumour development.
 

The role of IL-33 in development, brain injury and brain tumours

Grzegorz Wicher

IL-33 has important functions in inflammatory and autoimmune diseases (Enoksson et al, 2013). Little is known, however, about IL-33 in brain development, injury and brain tumours.

Our data suggest that IL-33 expression is under tight regulation in the normal brain but can be triggered by injury. Its detection during the first three weeks of postnatal life coincides with important parts of the CNS developmental programs, and opens the possibility of IL-33 involvement in normal developmental processes (Wicher et al, 2013). De novo expression of IL-33 after injury suggests involvement of this alarmin in the neuro inflammatory response (Wicher et al, 2017). A high level of expression in glioma samples implies a role in tumour development and progression.
 

Mast cells in brain metastasis

Ananya Roy

Brain metastases are becoming an important problem because of the progressive neurological disability and the lack of effective treatment due to the unique structure of the blood-brain-barrier (BBB). Recent studies in this field point towards a link between the immune system and metastases pathogenesis but many aspects still need to be investigated.

In order to clarify the role of MCs and other immune cells in brain metastasis we aim to understand the mechanisms underlying the MC-brain metastatic cell interactions and identify key factors regulating these interactions. Our preliminary data, for the first time, demonstrated the abundant accumulation of MCs in human brain metastases that originated from different primary tumours (lung, prostate, kidney, ovarian and rectum).

We want to study MCs contribution in the brain metastases microenvironment with specific focus on the role for MC proteases in this process. We plan to investigate MC-brain metastases (BM) cell interaction as well as their interaction with other infiltrating immune cells (in vitro studies), early stages of brain metastasis development, microenvironment regulation in BM (in vivo studies), as well as gather clinical data by exploring patient brain metastases samples and corresponding primary tumours. In our study, we aim to find potential biomarkers that will help in better understanding of this disease and thereby enable better diagnosis and treatment regimen.

The findings from this project aim to provide a new insight into the role of MCs and other immune cells in brain metastasis. Proper understanding of this interaction is a prerequisite in designing therapeutic protocols. The connections between immuno-regulation and metastatic microenvironment, will improve the treatment of brain metastases, and eventually prolong patient’s life.