Report on the funded project: Glioma-associated mesenchymal stem cells indicate new avenues for brain tumor therapy.
Application for the new research-project:
New pericytes in brain tumor blood-vessels originate from a previously unrecognized pericyte progenitor
Prof. Dr. Rainer Glaß, Leiter der Neurochirurgischen Forschung, Klinik für Neurochirurgie, Klinikum der Universität München, Marchioninistr. 15, 81377 München. Email: email@example.com
Report-period: 1 / 2016 until 12 / 2017
Glioblastoma (GBM) are aggressive, treatment-resistant primary brain tumours bearing histo-pathological hallmarks including high invasiveness and extensive vascularization. Despite these consistent morphological patterns GBM are also characterized by enormous heterogeneity, which is observed on different levels: 1. We find ample genetic diversity among tumours from different individuals as well as 2. large cell-biological and genetic differences within various regions of an individual tumour. We address these challenges, which impose major caveats for current therapeutic strategies for GBM, by investigating region-specific interactions of GBM cells with the tumour-supporting microenvironment and by including a range of genetically distinct GBM-models in our studies. Thereby, we observed that tissue stem-cells (mesenchymal stem cells; MSC), which can e.g. coordinate immune-reactions and healing-processes after wounding in the periphery, associate with GBM and promote pathological processes especially in invasive tumour parts. Here, MSC can strongly promote therapy-resistance and thereby facilitate GBM-relapse. We uncovered the molecular signalling mechanism of this propathological interaction and currently develop new treatment-concepts to blunt MSC-promoted tumour-recurrence. The extent of the MSC-contribution to unfavourable clinical outcome also depends on the genetic repertoire of GBM cells. We are classifying the genetic markers which inform on a pathologically relevant contribution of MSC to GBM and thereby obtain criteria for stratification of patients potentially profiting from new MSC-directed adjuvans therapies. We are completing this preclinical research project over the next months and will continue to inform the Anni Hofmann Stiftung on our progress. Also, we will initiate translational approaches to advance the clinical use of our findings. Currently, we propose a new basic science project to the Anni Hofmann Stiftung which has the potential to fundamentally advance current concepts for anti-angiogenesis in GBM. Clinically applied anti-angiogenic substances target signaling pathways in endothelia, which can cause adverse effects as endothelial cells are of ubiquitous importance throughout the body. We discovered a population of pericyte-progenitor cells, which is of vast importance for the formation of new intratumoural blood vessels and which is exclusively activated at the site of neoangiogenesis, namely in GBM. In our new proposal we aim to characterize these pericyte progenitors with the ultimate aim to make them accessible for pharmacological compounds that reduce GBM vascularization.