- Professor Paul Brennan paul.brennan@ed.ac.uk
- Dr Dirk Sieger Dirk.sieger@ed.ac.uk
- Dr Julie Mazzolini Julie.Mazzolini@ed.ac.uk
Funding information (students eligible to apply): UK/International students
Project Description
Glioblastomas represent a complex and devastating disease and are posing an unmet clinical need. These tumours resist multi-modal therapies and survival times are only 14 months on average. In recent years a lot of focus has been on the complex microenvironment of these tumours. Myeloid cells (microglia and infiltrating macrophages) are the most prominent cell types within the glioblastoma microenvironment and can account for up to 30-50% of the total tumour mass. These cells have been shown to promote tumour growth. However, little is known about the mechanisms that lead to the establishment and manifestation of these pro-tumoural activities within myeloid cells. Understanding the underlying mechanisms is crucial to prevent pro-tumoral activities of myeloid cells and to find ways to induce anti-tumoural activities.
We hypothesise that glioblastoma cells transfer miRNAs and proteins via EVs to myeloid cells, which results in gene expression changes inducing modification of myeloid cell morphology and functions. We speculate that these changes are key for the development of their pro-tumoural activities.
Extracellular vesicles (EVs) are membranous vesicles containing proteins, lipids and different RNA species that change the activity of recipient cells. Recent studies have shown EV release by glioblastoma cells, bringing EVs into focus as crucial mediators of the tumour microenvironment.
Over the past years we have established techniques to label EVs in a cell specific manner providing unpreceded insights into their release and uptake in vivo. Indeed, using a larval zebrafish model we can show release of EVs by glioma initiating cells and their uptake by microglia. Furthermore, RNA sequencing studies point to specific changes in human microglia upon incubation with EVs derived from different GBM subtypes. Here we aim to combine the expertise developed in the Sieger lab with the recently established human brain tumour slice culture of the Brennan lab. The Brennan lab has pioneered a platform for live human brain tumour slice culture. We use human brain tissue and tumour removed 2-3 time a week during surgery to interrogate tumour-non tumour cell interactions in the real, human, three-dimensional context. The 300um slices can be kept ‘alive’ for at least four weeks, and both tumour and non-tumour cells, including myeloid cells, imaged in the live cell culture. Intriguingly, this will allow us now to study EV release, uptake and their impact on recipient cells for the first time in living human brain tumour samples. Based on this model and our combined expertise, we plan to address the following objectives:
- Live imaging of EV release from glioblastoma cells and their uptake by myeloid cells
- Analysing EV content and function
- Analysing the role of candidate miRNAs/proteins transferred by EVs and their impact on myeloid cells and tumour growth
References
- Ezgi Kiyga, Katy Reid, Guillaume van Niel, Julie Mazzolini and Dirk Sieger. Advanced Methods for Isolation and Cell-Specific Labelling of Extracellular Vesicles from Larval Zebrafish. 2025 Journal of Extracellular Vesicles, under revision
- Mazzolini J, Le Clerc S, Morisse G, Coulonges C, Zagury JF, Sieger D. Wasl is crucial to maintain microglial core activities during glioblastoma initiation stages. Glia. 2022 Jun;70(6):1027-1051. doi: 10.1002/glia.24154
- Kelda Chia, Marcus Keatinge, Julie Mazzolini and Dirk Sieger. Brain tumours repurpose endogenous neuron to microglia signalling mechanisms to promote their own proliferation. eLife; 2019 Jul 17;8.
Categories
Biological Sciences
Cancer Biology; Cell Biology; Molecular Biology; Neuroscience;
Medicine
Pathology;