• We recently demonstrated - using a patient-derived glioblastoma resection model - that surgery leads to early recurrences having more tumor-associated microglia and macrophages (TAMs) and being more aggressive than primary glioblastomas. This involves pleiotrophin-mediated self-renewal of glioblastoma stem cells in recurrent tumors. Knudsen et al, Neuro Oncology, (2022), PMID: 34964899 doi: 10.1093/neuonc/noab302​
  
  
• We found that a high amount of TAMs expressing CD204 is associated with poor prognosis in patients receiving chemotherapy. Sørensen et al, NAN, (2018) PMID: 28767130 DOI: 10.1111/nan.12428 
  
  
• ​​Our data showed that MGMT protein expression in tumour cells has an independent prognostic significance in glioblastoma and that exclusion of nontumour cells from the analysis contributed to a more exact analysis of tumor-specific MGMT protein expression. Dahlrot et al, NAN, (2018) PMID: 28574607 DOI: 10.1111/nan.12415
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Spatial insight into the microenvironment

• We recently demonstrated – using spatial profiling – that a differential expression pattern of checkpoint markers exists in the normoxic and hypoxic microenvironment of glioblastomas. This may have therapeutic implications. Petterson et al, Brain Pathology, (2023), PMID: 36093941 

• In another study we found that tumour-associated CD204+ microglia/macrophages accumulate in perivascular and perinecrotic niches and correlate with an interleukin-6 enriched inflammatory profile in glioblastoma, Sørensen et al, NAN, (2022), PMID: 34713474 DOI: 10.1111/nan.12772
   

Mutational profile influences the microenvironment

• D 2-HG in IDH-mutant astrocytic gliomas suppresses the host immune system, potentially by promoting immune escape of IDH-mutant tumors. Zhang et al, Clin Cancer Research (2018) PMID: 30006485 DOI: 10.1158/1078-0432.CCR-17-3855 

• We showed that IDH mutation is associated with diminished levels of TIM-3⁺ cells and fewer interactions between TIM-3⁺ T cells and galectin-9⁺ microglia/macrophages, suggesting reduced activity of the galectin-9/TIM-3 immune checkpoint pathway in IDH-mutant astrocytic gliomas. Sørensen et al, Brain Pathology (2020). PMID: 33244787  DOI: 10.1111/bpa.12921
   

Migrating glioma cells and aggressiveness

• We have demonstrated that migrating peripheral glioblastoma cells give rise to new brain tumors upon xenografting supporting that this cell population is of critical importance. Munthe et al, JNO (2016) PMID: 27510953 DOI: 10.1007/s11060-016-2221-y

• Migration of glioblastoma cells into  organotypic brain slice cultures mimics tumor cell invasion into the brain in vivo. Jensen et al, PLoS One (2016) PMID: 27454178 DOI: 10.1371/journal.pone.0159746

• We demonstrated that EGR3 may be implicated in cell migration in glioblastoma. Knudsen et al, Scientific Report (2020) PMID: 32518380 DOI: 10.1038/s41598-020-66236-x
  
  

Identification of novel therapeutic strategies for brain cancer with spatial profiling of the hypoxic niche

Glioblastomas are characterized by extensive areas with hypoxia, peri-necrotic palisades and microvascular proliferation, which are diagnostic hallmarks of glioblastoma. These aspects are part of the hypoxic niche in glioblastoma and has been associated with stem-like cells and therepeutic resistance. In this project we hypothesize that the tumor-associated microglia and macrophage (TAM) rich microenvironment of the hypoxic niche with both hypoxic TAMs and tumor cells support a TAM and/or tumor cell phenotype, that express novel therapeutic targets, which can be targeted and lead to improved survival in a pre-clinical glioblastoma model with tumor resection and recurrence. Methodologically we will use spatial profiling of these cell populations covering the full spectrum of cells from the hypoxic niche to microvascular proliferations.

Therapy resistance in glioblastoma and microenvironment

The aim of this project is to interrogate the existence and characteristics of different clinically important TAM subtypes in glioblastoma and to experimentally target novel TAM-related therapeutic candidates. We are using RNA single-cell sequencing (scSeq) on isolated TAMs from fresh patient glioblastoma tissue and validation by histological high-end biomarker multiplexing with metal-tagged antibodies (Imaging Mass Cytometry). Impact of candidate targets on patient survival are investigated by well annotated patient cohorts including a cohort used for an international multicenter trial. scSeq has revealed the existence of tumor promoting TAM subtypes, which we now validate and investigate functionally. 

Improved pre-clinical models

Novel therapies are rarely investigated in the context of tumor resection in preclinical models - although chemo-radiation therapy is given after resection in patients. However, early recurrent patient glioblastomas contain a high amount of inflammatory and reactive cells, which interact with and affect tumor cells. The aim of this project is to use a novel improved pre-clinical model with tumor resection to interrogate the tumor cell phenotype and the microenvironment in early glioblastoma recurrences in order to identify and test potential novel targets. 

Bjarne Winther Kristensen (MD, PhD) is professor of Pathology with research focus on brain cancer.

The overall aim of his research group is to better understand the molecular pathology and microenvironment of brain tumors in order to come closer to precise diagnostics and personalized therapy.

The expertice of his research group covers spatial profiling, immunohistochemical multiplexing, digital pathology and quantification of biomarkers, in vitro and in vivo brain cancer models and a series of techniques ranging from sequencing, genome-wide methylation profiling, transfection, confocal time-lapse microscopy to western blot. 

His research group emphasizes the translational aspect in their research. Their experimental research is based on brain cancer tissue from patients and the establishment and use of well annotated patient cohorts play an important role in their biomarker studies.

Professor Bjarne Winther Kristensen is Vice-President in Euro-CNS and Past President of the Scandinavian Neuropathological Society (2013-2016 and 2019-2022). He was Congress President and main organizer of the 12th European Congress of Neuropathology 2021.

​Professor Bjarne Winther Kristensen is also chief physician at Rigshospitalet-Copenhagen University Hospital.

Publications

All publications

​Master thesis projects, PhD projects and other types of research projects​

Professor Bjarne Winther Kristensen receives grant (DKK 1.905.385)from NEYE-Foundation for the project: Targeting glioblastoma recurrence by novel insight into the post-surgical microenvironment in patients​

We host the 12th European Congress of Neuropathology with Professor Bjarne Winther Kristensen as Congress President

Read more here: http://www.ecnp2021.dk/

Funding sources