Online Ph.D Defence by Johann Mar Gudbergsson
Johann Mar Gudbergsson will defend his PhD thesis: “Understanding Glioblastoma stem-like cells in quest of a target to direct treatment”
09.06.2020 kl. 12.00 - 15.00
12.00 Opening by the Moderator
12.05 PhD lecture by Johann Mar Gudbergsson
13.00 Questions and comments from the Committee
Questions and comments from the audience at the Moderator’s discretion
15.00 Conclusion of the session by the Moderator
Due to the current circumstances the Ph.D defence will take place online via Skype for Business. If you wish to attend, please send an email to Kristine Uldal Knudsen before 05. June 2020 at 12:00.
The Faculty Council has appointed the following adjudication committee to evaluate the thesis and the associated lecture:
Head of Surgical Neuro-oncology Einar Osland Vik‐Mo
Associate Professor Marie Kveiborg
University of Copenhagen
Professor Karen Dybkær
Aalborg University Hospital
Associate Professor Trine Fink
Glioblastoma multiforme (GBM) is the most common and deadly tumor of the central nervous system with a median overall survival of only 12-15 months from time of diagnosis. Treatment consists of maximum safe resection surgery followed by radio- and chemotherapy. Despite this heavy treatment tumor recurrence remains ubiquitous with the recurrent tumors being more aggressive and resistant to treatments, underscoring the need for better understanding of GBM biology and improved treatment strategies for GBM patients. GBM tumors are highly different from each other and within each tumor a high location-dependent heterogeneity exists. On a cellular level, a tumor cell hierarchy is formed partially in resemblance to that of a normal organ, with GBM stem cells (GSC) at the apex orchestrating the tumor growth and composition. GSCs exploit pathways that are highly active during normal embryonal development, including functions such as cellular migration, asymmetric cell division and cellular differentiation.
In this thesis, the objective was to identify proteins on GSCs to direct treatments towards these hard-to-reach cells. We have here included four manuscripts that represent the fundament of our research to achieve this goal. Initially, we had identified cripto-1 as a potential target towards GSCs and investigated its subcellular localization in an overexpression model to see where this protein might be situated in order to evaluate whether it could be used as a target. We showed that cripto-1 was mainly localized to the plasma membrane and was highly present in membrane-derived filopodia structures. Next, while examining cripto-1 in wildtype (non-overexpressed) GBM cells, we saw some unexpected binding of the cripto-1 antibodies used. This led to an evaluation of four different cripto-1 antibodies, reporting different results from each of these antibodies, and thus a discontinuation of cripto-1 research was decided.
In order to better identify new and relevant targets, we needed more translatable GBM cellular models for both in vitro and in vivo studies. Here, we characterized a patient-derived tumorsphere model that showed intercellular heterogeneity both in vitro and in vivo and could be used for therapeutic assessment in vitro. Next, we expanded on this model and set up a larger in vivo study where we examined how conventional GBM treatments (radiotherapy and temozolomide) affected the cellular composition of the GBM tumors. Through multicolor flow cytometry and FlowSOM clustering analysis, we showed that an upregulation of CD44 was seen in all treatment groups compared to the untreated group. This could indicate that CD44 could become a target for future directed treatments, however, we still have a long road ahead of us. In the overall discussion presented in this thesis, we cover some contextual topics that include modeling of GBM tumors and targeting GSCs.
HST - Department of Health Science and Technology
Skype for Business
05.06.2020 kl. 12.00