New Ultrasound Technique Watches Glioblastoma Build Its Nest in Mouse Brains

When you settle somewhere new, one of your earliest impulses may be to make a comfortable nest: a personal space arranged precisely to your liking.

Cancer, it seems, can behave in a disturbingly similar way.

As a tumour develops, it reshapes the environment around it for its own purposes. It forces tissue aside, remodels blood vessels and commandeers the body's processes to sustain its survival and expansion.

Scientists have now created an ultrasound method that lets them observe this nest-building process as a lethal tumour establishes itself deep within a mouse's brain.

The tumour in question is glioblastoma, and the way it makes a home for itself could provide insights into how it might be fought.

"The ability of our platform to capture all three dimensions of tumor progression in vivo in awake animals represents a major step forward in studying neuro-oncological processes with spatiotemporal precision and developing improved treatments," writes a team led by Caltech chemical engineer Mikhail Shapiro in a study published in iScience.

Glioblastoma and its impact on the brain

No cancer is benign, but certain forms are particularly aggressive. Among them are gliomas: usually malignant tumours that originate in glial cells, or their precursor cells, in the brain or spinal cord.

Glioblastoma is the most severe type, with a five-year survival rate of only 5 to 7 percent.

Gliomas are difficult to treat in part because they exploit essential brain functions for their own benefit. They become tightly intertwined with healthy surrounding tissue and blood vessels, using them to support their survival.

Working out exactly how this happens is also challenging. The brain is an exceptionally intricate and highly organised organ. Researchers cannot simply probe it to discover how it works, since even animal-model experiments can cause damage that alters the very processes under observation.

Non-invasive imaging technologies can offer a view inside a living brain, but they too have restrictions.

Magnetic resonance imaging (MRI), for instance, can scan the entire brain and follow both tumours and blood vessels, yet it is not particularly suitable for examining brain function in awake, behaving animals. Optical imaging can provide remarkable detail, but it cannot reach far into brain tissue.

No individual technique, meanwhile, can give scientists every measurement they need simultaneously.

"Critically," the researchers write, "no existing modality captures tumor growth, vascular remodeling, and the hemodynamic correlates of neural activity together within a single, co-registered acquisition at comparable spatial resolution and depth."

A trimodal ultrasound technique for glioblastoma

The researchers therefore set out to unite three approaches in one ultrasound system, enabling it to capture more of glioblastoma's development than earlier methods had managed.

Their first challenge was making glioblastoma distinguishable from the brain tissue surrounding it in ultrasound scans.

They addressed this with an ingenious piece of biological engineering. Certain bacteria naturally create tiny gas-filled bubbles called gas vesicles. The team cultured human glioblastoma cells, then equipped them with the bacterial genes responsible for producing these bubbles.

Next, they placed the glioblastoma cells in a hydrogel phantom: essentially a tissue-like material used to establish whether the bubbles would make the glioblastoma material more visible under ultrasound.

That test succeeded. The remaining task was to put the cells into a brain. Igor, fetch the mice.

To evaluate the technology in living brains, the team implanted the engineered human glioblastoma cells into the left thalamus of three mice.

Over the following 11 days, they repeatedly used trimodal ultrasound to monitor the tumours as they became established and enlarged.

One mode used the gas vesicles to identify the tumour itself. A second followed blood-volume shifts linked to brain activity. The third relied on minute bubbles injected into the bloodstream to map, in exceptional detail, the network of blood vessels around the tumour.

Impressively, the method appeared to perform as intended.

The mice were scanned while awake and able to move on a padded platform, although their heads were held in place to limit wriggling.

As the tumours increased in size, the researchers could follow them physically pushing the nearby lateral geniculate nucleus (LGN), which handles visual information, away from its usual position.

Meanwhile, the rise in blood flow that normally accompanies LGN activity when a mouse sees something was reduced on the affected side. However, this decrease was statistically significant in only one mouse; in another, it occurred on both sides.

Blood vessels and brain activity around the tumour

The growing tumour also appeared to reorganise the brain's plumbing. Vascular scans, obtained while the animals were under anaesthesia, showed blood vessels being moved and rearranged around the expanding tumour.

In the single mouse for which a full dataset was available, blood travelled more slowly through vessels surrounding the tumour. There were also indications that some vessels were narrowing or becoming blocked.

The tumour further appeared to form a small world of its own inside the brain.

Blood volume rose and fell across the nearby brain in coordinated patterns, but the tumour followed a rhythm of its own, seemingly disconnected from the activity around it.

At present, however, it is not possible to determine precisely what this activity represented or why it occurred.

The study's purpose was to establish whether the technique could monitor glioblastoma-related changes in awake, living mice at a fine level of detail.

Determining the significance of those changes, and whether they are consistent in a larger group of subjects, will require additional research.

There are major limitations to consider. This was a proof-of-concept study involving only three mice, and it used a glioblastoma model that does not recreate all the complex realities of the disease in humans.

The next stage is to assess the technique in more animals and in brain-cancer models that better reflect reality, to find out whether the unusual patterns seen by the researchers persist.

Future studies could also use the approach to observe the effects of treatment: not merely whether a tumour gets smaller, but how the brain and blood vessels entangled with it react.

Ultimately, the researchers hope that seeing glioblastoma construct its nest will reveal how to dismantle it, twig by vicious twig.

The research has been published in iScience.

This article was fact-checked by Rebecca Dyer and edited by Rebecca Dyer. Although we take pride in our process, we are only human. If you notice an error, please let us know.