Brain cancers are some of the most devastating and difficult to treat diseases imaginable. The brain is a dangerous place to operate, and many brain cancers do not respond to traditional chemotherapy drugs because of the brain’s natural defenses. Like the brain itself, cancers of the brain are poorly understood. New insights came recently from three papers published by three separate research groups in the journal Nature. They all report related findings that show cancerous cells forming connections with neurons and using neuron-like signaling to grow more dangerous.

Studies led by Venkataramani and Venkatesh looked at high-grade gliomas either grown in the lab or implanted into mice. Gliomas are cancers of glial cells, the cells found in the brain that support neurons. It was known that these particularly aggressive cancers are sensitive to the ‘microenvironment’ – the surrounding conditions including growth factors and ions – but it was not previously appreciated that gliomas form neuron-like connections, “synapses”, with brain cells. This discovery was driven largely by technological advancements that let researchers peer more closely than ever before at individual cells. There is a limit to how much microscopes can magnify an image. This means that even if glioma cells were placed under the best microscope, the structures that make up the “synapse” or connection would be too small to see. To get around this limit, Venkatesh et al. use electron microscopy, which uses electrons instead of visible light for imaging because electrons have much smaller wavelengths. Alternatively, the Venkataramani group used a kind of “super-resolution” microscopy, a method that can computationally reconstruct very small structures from a series of images taken of fluorescently labeled cells. Both techniques allowed the researchers to see structures that had never been observed on glioma cells before, structures that resemble those that connect neurons to each other.

Both of these studies show evidence that synaptic connections are driving cancer growth and invasiveness. These results were supported by molecular profiling that showed signatures of neuronal synapses. They were able to show that drugs that prevent neuronal activity remove this effect and that artificially activating cells with light increased invasiveness. In parallel, Zeng et al. investigated whether cancers that start in other parts of the body display the same synapses once they migrate to the brain. Using similar super-resolution imaging and molecular profiling, they found that breast cancer cells that migrated to the brain also connections with neurons that stimulate their growth. This is particularly interesting because it shows the extent to which cancer cells can adapt to the environment around them.

As scary as it is to think that cancer cells can grow faster because of brain activity, these findings suggest new therapeutic approaches. For example, many drugs that treat epilepsy could help treat glioma by dampening these overactive neuronal signals. This is another example of how our growing molecular understanding of cancer is continuing to improve treatment.

Managing correspondent: Julian Segert

Press articles: Deadly Brain Cancers Act Like ‘Vampires’ By Hijacking Normal Cells To Grow NPR

Brain tumors form synapses with healthy neurons, study finds Medical Xpress

Original articles: Glutamatergic synaptic input to glioma cells drives brain tumour progression Venkataramani et al. Nature

Electrical and synaptic integration of glioma into neural circuits Venkatesh et al. Nature

Synaptic proximity enables NMDAR signalling to promote brain metastasis Zeng et al. Nature

Image: Seung Lab/ Flickr

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