Extracellular matrix interactions of importance for brain tumor formation

In our projects we incorporate experience of neural stem cells with glioma biology, leveraging the close relationship between these two fields. We focus on the tumor microenvironment with special emphasis on the extracellular matrix and the neuro-inflammatory responses to brain tumors.

Aim

The overall goal of our research is an improved treatment of malignant brain tumors, in particular glioblastoma and medulloblastoma.

Background

The tumor microenvironment (TME) is composed of several cell types and an altered extracellular matrix (ECM). The ECM is a complex network of macromolecules, such as proteins, glycosaminoglycans, glycoproteins, and proteoglycans. These are assembled into organized structures with distinct roles in regulating proliferation, cell survival, differentiation to mature cell types, migration and invasion. The focus of this project is the “brain tumor niche” that allows tumor cells to detach from the original site, remodel the extracellular matrix (ECM) and migrate to seed new tumors which has severe consequences for the patient. ECM molecules are emerging as important regulators in the TME, and their composition is often distinct from that of the normal brain. Understanding the ECM of brain tumors has been proposed as one of the recent challenges in the path to cure primary brain tumors. We focus on proteoglycans (PGs), an important component of the ECM.

Heparan sulfate (HS) proteoglycans (HSPGs) are one of the main components of the ECM where they interact with a large number of physiologically important macromolecules, thereby influencing biological processes. HS modulate growth factor activities, and we have shown a vital role for HS in neural stem cell differentiation 1,2. The project aims to better understand the role of HS and related pathways in glioblastoma (GBM) and other childhood brain tumor development 3,4. We also aim to identify PGs that correlate to therapeutic resistance in these diseases.

Possibilities and techniques to pursue in this project:

• In vitro cell culture and related: e.g. culturing of primary stem-like tumor cells, gene editing of stem-like tumor cells, various cell assays like growth, proliferation, invasion, sphere formation etc.
• Molecular biology techniques: e.g. cloning, protein quantification, characterization, identification (western blot), DNA and RNA extraction, genotyping, QPCR, ELISA, enzymatic assays etc.
• Staining and imaging: e.g. immunofluorescence (IF/ICC), immunohistochemistry (IHC) staining of tissue /cells, imaging and quantification analysis using image analysis softwares.
• Bioinformatics, biostatistics and data mining: e.g. Profiling of proteoglycans in GBM and other CNS tumors based on data from publicly available databases, correlation analysis, parametric analysis for treatment dynamics, pathway analysis etc.
  

Contact details

Karin Forsberg Nilsson
E-mail: karin.nilsson@igp.uu.se
Phone: 018-471 4158 or 070-1679579

References

1. Xiong, A., et al. Heparanase confers a growth advantage to differentiating murine embryonic stem cells, and enhances oligodendrocyte formation. Matrix biology : journal of the International Society for Matrix Biology Oct;62, 92-104 (2016).
2. Kundu, S., et al. Heparanase Promotes Glioma Progression and Is Inversely Correlated with Patient Survival. Molecular cancer research : MCR 14, 1243-1253 (2016).
3. Spyrou, A., et al. Inhibition of Heparanase in Pediatric Brain Tumor Cells Attenuates their Proliferation, Invasive Capacity, and In Vivo Tumor Growth. Molecular cancer therapeutics Aug;16(8), 1705-1716 (2017).
4. Xiong, A., Roy, A., Spyrou, A. and Forsberg-Nilsson, K. Heparan sulfate in normal and cancer stem cells of the brain. M. Götte and K. Forsberg-Nilsson, editors, Proteoglycans in stem cells. From development to cancer, Biology of Extracellular Matrix,volume 9, Springer Nature, 205-236, ISBN: 978-3-030-73452-7, 2021
5. Xiong, A., Spyrou, A. and Forsberg-Nilsson, K. Involvement of heparan sulfate and heparanase in neural development and pathogenesis of brain tumors. I. Vlodavsky, R. Sanderson and N. Ilan, editors, Heparanase - From basic research to clinical applications, Adv Exp Med Biol. 2020;1221:365-403. doi: 10.1007/978-3-030-34521-1_14.