Researchers have uncovered a set of hidden rules that glioblastoma brain tumours follow as they grow, potentially paving the way to more effective treatments.

To make the discovery, an international research team used AI tools and state-of-the-art cell-tracking technologies to map and characterise more than a million cells from 12 people being treated for glioblastoma.

By looking at each cancer cell’s inner workings and external environment at different points in time, they were then able to trace a predictable structural pattern that seems to connect all glioblastomas.

That came as a surprise, to say the least. Cancer is usually thought of as chaotic, uncontrolled growth, and glioblastoma is one of the hardest types to contain and treat. It’s made up of a diverse mix of cancer cells with different ways of resisting or avoiding drugs and radiotherapy. Until now, scientists haven’t been able to find any consistent rules or patterns to explain it.

“For too long, we’ve approached glioblastoma treatment knowing that each patient’s tumour contains a complex mixture of cancer cells, but without a clear understanding of how best to target them all,” said Dr Richard Mair, a brain surgeon and researcher at the Cancer Research UK Cambridge Institute.

But the team’s findings, published today in the scientific journal Nature, suggest that it could be possible to stop glioblastoma from following its predetermined paths.

“This research gives us an opportunity to think differently,” said Mair. “If we can anticipate the different biological states a tumour is likely to adopt, we can begin to develop treatments that target multiple aspects of the disease from the very beginning.

“This could fundamentally change how we design new therapies for glioblastoma, moving towards treatments that are informed not just by what a tumour looks like today, but by what it is likely to become.”

The patients and the pattern

Twelve glioblastoma patients at Cambridge University Hospitals NHS Foundation Trust, where Mair also works, donated tumour tissue to make this research possible.  

The team then used state-of-the-art “omics” technologies and AI tools to track each cancer cell’s molecular state, location, chances of changing, interactions with its surrounding environment, and DNA. They also checked their findings using lab-grown mini-brains, or brain organoids.

This allowed the team to see that, despite their chaotic diversity, all glioblastoma cells moved through the same three-step pattern. 

1. At first, glioblastoma cells resemble brain stem cells, which generate new neurons as we develop. These early cells gather at the outer edge of the growing tumour, where they can give rise to other cancer cell states.
2. Then, as the tumour expands, early cells shift into injury response cell states, mimicking cell pathways that are involved in brain tissue repair and wound healing to multiply more quickly. As the leading edge of the tumour keeps moving, the injury response cells also form an inner structural layer in the tumours.
3. In glioblastoma’s later stages, the core of the tumour is cut off from oxygen, pushing the inner cells into survival states, which can be very resistant to treatments.   

In another paper, some of the researchers decoded the genetic drivers and switches that triggered these transitions. They believe that new drugs designed to block these triggers could lock glioblastoma cells into specific states, making them more vulnerable to other treatments.   

The research also showed that each of the three stages is supported by a specific microenvironment, which the tumour creates by co-opting the body’s protective immune cells. It’s also possible that treatments could be designed to disrupt this part of the process

And, as Mair highlighted, other new options could focus on targeting the early developmental cells on the tumour’s edge, as these can’t always be removed by surgery and often lead to cancer recurrence. 

A new era of glioblastoma research

The team have made their full picture of glioblastoma available through the GBM-Space atlas, which is free to access. Researchers around the world can use it to keep building on this discovery and finding out more about the mechanisms and biology of cancerous brain cells.

“Glioblastoma has evaded understanding for years, despite being one of the most studied types of cancer tumour,” said Dr Omer Bayraktar, co-senior author of the study at the Wellcome Sanger Institute. “By building the largest multi-modal atlas of these tumours to date, we’ve shown that these tumours are not as chaotic as previously accepted. Instead, they follow a set of rules that can be used to rewrite our understanding of glioblastoma and act as a compass to guide much-needed new treatments in the future.”

It’s the beginning of a long journey, but now researchers know the path to follow. As Dr Marianne Baker, a research information manager at Cancer Research UK, put it: “This is early research, but it could help guide the development of treatments that target more of the tumour and keep cancer under control for longer, giving people more time with their loved ones.”