Glioblastoma is one of the deadliest human cancers, with most patients surviving just 12 to 15 months from diagnosis. There is no treatment that is effective in the long-term.
In this project, Dr Dirk Sieger and colleagues aim to understand how glioblastoma influences immune cells to make them promote its own growth.
Following rigorous assessment as part of our competitive grant round, this project was recommended for its strong potential to advance understanding of glioblastoma. Based on solid preliminary data and driven by a collaborative and highly qualified team, this innovative and exciting project has clear potential for clinical translation.
Glioblastoma is the most common primary brain cancer in adults, with around 2,500 cases diagnosed every year in the UK.
It is a grade 4 tumour, meaning that it grows and spreads quickly. It infiltrates the brain, wrapping finger-like tentacles around vital brain structures, making complete surgical removal impossible.
The current treatment strategy includes surgery to remove as much tumour as possible, followed by radiotherapy and chemotherapy to destroy remaining tumour. This prolongs survival but is not curative. Only a quarter of patients survive more than a year from diagnosis.
The need for new treatments is urgent.
Read more: About brain tumours
Glioblastomas are recognised by the immune cells of the brain, the microglia. But unfortunately, rather than fighting the brain tumours, the microglia have been shown to actively promote their growth. This is disastrous behaviour and we don’t understand why it happens.
Microglia are dynamic cells that normally show a constantly changing ramified cellular shape, and exhibit key functions such as motility (spontaneous movement) and phagocytosis (ability to engulf and digest harmful cells and bacteria).
In pioneering work using zebrafish models, Dr Sieger and colleagues have shown that microglia lose their typical ramified shape during their response to tumour-initiating cells, and show impaired motility and phagocytosis. Their reduced phagocytosis protects tumour cells from engulfment, while their impaired motility results in the microglia being retained within the tumour microenvironment where they develop their tumour-promoting activities.
The cause of these microglial changes is not known but the team speculates that they are caused by the uptake of small particles known as extracellular vesicles (EVs), released by the tumour-initiating cells. They have already observed this process in their zebrafish model.
They believe that the EVs transfer genetic material from the tumour-initiating cells to the microglia, causing the change of shape, and a decrease in their motility and phagocytic capacities.
In this project, they will perform high-resolution microscope live imaging to visualise the release and uptake of EVs during glioblastoma initiation stages in their zebrafish model. They will interfere with the release and uptake, and analyse how this impacts on microglia.
They will study the content and function of EVs from zebrafish and mouse glioblastoma initiating cells as well as human glioblastoma cells, to test their hypothesis that the content of these EVs targets specific genes in microglia that are crucial to maintain their ramified shape, and normal function.
Microglia are extremely sensitive cells. They show their normal function and behaviour only in their natural environment, the brain. Hence their function cannot be studied in test tubes – only in the living brain.
Zebrafish have become powerful discovery tools for human disease in recent years. They share 71% of human genes (82% of disease-related genes), and offer superb imaging opportunities due to the transparency of the larva, allowing monitoring of biological events in real time and in situ.
This project uses larval zebrafish, at an early stage of development. Their use was reviewed as part of the application process and the team has the necessary approvals to conduct this work.
Read our policy on the use of animals
Glioblastoma is one of the most devastating forms of cancer. It has no treatment that is effective in the long-term, and most patients die within 12 to 15 months of diagnosis. New treatments are desperately needed.
Since microglia play a crucial role during tumour growth and tumour invasiveness, these cells are promising targets for therapy. Understanding exactly how microglia are transformed from anti-tumour to pro-tumour is the necessary first step to find treatments to inhibit this transformation.
The work being carried out by Dr Sieger and colleagues aims to find treatments that change the activities of microglia specifically in the tumour environment, with the goal to convert microglial activities and make them fight the tumour. To achieve that, their zebrafish model system provides an easy platform to test the effect of novel drugs.
“If successful, this project has the potential to provide new insights into the mechanisms that lead to the pro-tumoral activities of microglia, which could ultimately lead to new prospects for therapeutic intervention in humans.” External reviewer
Dr Sieger is one of the leading scientists in zebrafish microglia biology and has pioneered the use of larval zebrafish to understand how the function of microglia changes within a growing brain tumour.
The University of Edinburgh is one of the UK’s foremost centres for brain tumour research and Dr Sieger and co-applicant Dr Julie Mazzolini will collaborate locally with world-leading experts in glioblastoma and internationally with experts on exosome biology and sequencing data analysis in France.
Together this highly collaborative team are well-placed to succeed in the delivery of this important work.
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