Our scientific goal is to obtain a deeper understanding of brain cancer and thereby to discover novel promising therapeutic approaches for glioblastoma patients.
The Kristensen Group is located at the Bartholin Institute, which is part of Department of Pathology at Rigshospitalet, Copenhagen University Hospital.
Glioblastoma is the most frequent and malignant type of brain cancer and most patients have a poor survival. Novel therapeutic strategies that overcome the efficient mechanisms of resistance are urgently needed. Our aim is to identify, understand and overcome mechanisms of resistance in the microenvironment of glioblastomas. The microenvironment is heterogenous leading to potentially different mechanisms of resistance in the core and periphery of glioblastomas. Adding to the complexity, there is a high frequency of non-tumor cells in glioblastomas leading to potential critical cross-talk between tumor cells and microglial cells and macrophages and other cell types. Having identified novel clinical relevant targets taking the interaction between tumor cells and the microenviroment into account, we can turn this knowledge against the glioblastoma from a therapeutic point-of-view.
Microenvironment and prognosis
- We found that a high amount of tumor-associated microglia and macrophages (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
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
Therapy resistance in glioblastoma and microenvironment
Tumor-associated microglia and macrophages (TAMs) comprise up to 30% of cells in glioblastomas. TAMs interact with and affect tumor cells, but the existence of different TAM subtypes is only incompletely understood. The aim of the present 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.
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.
We use brain cancer tissue from patients for in vitro and in vivo models, transfection, confocal time-lapse microscopy, Western blotting, PCR, flow cytometry as well as single cell sequencing.
To discover novel biomarkers in order to be able to make more precise diagnoses and to be able to predict survival and effect of therapy, we use patient cohorts, immunohistochemistry, computer-based biomarker analysis, NGS, genome wide methylation profiling, mRNA profiling and proteomics.
The better understand the role of the spatial organization of cells and tissue compartments in brain tumor tissue, we use immunofluorescence multiplexing and deep spatial profiling as important techniques. We have established and use the two core facilities below for these studies. The core facilities are open to all users, who can benefit from these techniques.
- The Vectra Polaris Imaging system for immunofluorescence multiplexing. The core facility is localized in the Bartholin Institute.
- The Nanostring GeoMx platform for deep spatial profiling. The core facility is localized in the Bartholin Institute.
M.D. Sørensen, R.H. Dahlrot, H.B. Boldt, S. Hansen and B.W. Kristensen. Tumor-associated microglia/macrophages predict poor prognosis in high-grade gliomas and correlate with an aggressive tumor subtype. Neuropathol Appl Neurobiol, Feb;44(2), 185-206, 2018. PMID 28767130.
BW Kristensen, LP Priesterbach-Ackley, JK Petersen and P Wesseling. Molecular Pathology of Tumors of the Central Nervous System. Ann Oncol. Aug 1;30(8):1265-1278, 2019. PMID 31124566.
LP Priesterbach-Ackley*, HB Boldt*, JK Petersen*, N Bervoets, D Scheie, BP Ulhøi, M Gardberg, T Brännström, SH Torp, E Aronica, B Küsters, WFA den Dunnen, FYFL de Vos, P Wesseling*, WWJ de Leng* and BW Kristensen*. Brain tumour diagnostics using a DNA methylation-based classifier as a diagnostic support tool. Neuropathol Appl Neurobiol Aug;46(5):478-492, 2020. *Shared first and last authorship PMID 32072658.
JK Petersen, HB. Boldt, MD. Sørensen, S Blach, RH Dahlrot, S Hansen, M Burton, M Thomassen, T Kruse, FR Poulsen, L Andreasen, H Hager, BP Ulhøi, S Lukacova, G Reifenberger and BW Kristensen. Targeted next-generation sequencing of adult gliomas for retrospective prognostic evaluation and up-front diagnostics. Neuropathol Appl Neurobiol. Jul 21, 2020, [Epub ahead of print], PMID: 32696543
SA Petterson, MD Sørensen and BW Kristensen. Expression profiling of primary and recurrent glioblastomas reveal a reduced level of pentraxin 3 (PTX3) in recurrent glioblastomas, Journal of Neuropathology and experimental Neurology, Sep, 1;79(9):975-985 2020, PMID: 32791527
MD Sørensen, O Nielsen, G Reifenberger and BW Kristensen. The presence of TIM-3 positive cells in WHO grade III and IV astrocytic gliomas correlates with isocitrate dehydrogenase mutation status. Brain Pathol. 2020 Nov 26 Online ahead of print. PMID: 33244787
Kristensen group hosts the 12th European Congress of Neuropathology with Professor Bjarne Winther Kristensen as Congress President
In the media
- November 2016