Cancer Cells Travel to the Brain and Form Connections with Neurons: How cancer cells colonize the brain

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Unmila P. Jhuti, PhD

Brain metastasis is the deadliest yet least understood type of metastasis. Recent research showed that some tumors not only survive in the brain atmosphere, but can also form synapse-like connections with neurons. This way, the tumor cells can activate the growth-promoting signals in themselves. In this article, we are going to learn how tumor cells adapt, form neuronal synapse contacts using several molecular mechanisms, and how humans are going to handle this information in terms of therapy.

What are these synaptic contacts, and why are they important?

The most common function of the synapses is that they connect one neuron to the next and help neurons in communication, neurotransmission, and signal transduction. When cancerous cells invade the brain, they act like chameleons- they form pseudo-synapses with the neurons, camouflage their true selves, and start acting like neurons. Several research articles confirmed this phenomenon. For example, metastatic breast cancer cells formed synaptic connections with the primary excitatory neurons known as the glutamatergic neurons. Electron microscopy in this study showed tumor cells placed themselves next to the axon-dendrite connection (Article). This means that the cancer cells locate themselves exactly where the neurotransmitters get released, hijack the signaling pathway, and possibly use the signal for their proliferation. Cells metastasized from lung cancer showed a connection with neurons capable of transmitting electrical signals (Article). Researchers found that the tumor cells became a part of the neural circuits by establishing synaptic connections with the adjacent neurons and by receiving electrical signals to help with their growth.

Tumor cells that invade the synaptic connection and colonize the brain do this for their own benefit. Synaptic connections enable them to receive trophic signals from neurons, promoting growth or survival, and protect them from immune surveillance. 

So how do they do it?

After invading the brain, cancer cells increase the production of receptors that are often found in neurons. This is essentially a camouflage to act as a neuron. Although after expressing receptors, they often cannot produce enough neurotransmitters like a neuron. In breast-to-brain metastases, cancer cells express glutamate receptors but do not secrete enough glutamate themselves. Through making synaptic connections with neurons cancer cells are able to increase this secretion, possibly by convincing the preceding neurons to release more glutamate (Article). Cancer cells in the brain often express cell‐adhesion molecules such as neuroligins, neurexins and place them close to neuronal terminals to lure neurons in (Article). They can also replace glial cells called astrocytes in the tri-synapse setting of neuron–astrocyte–neuron. After the establishment of synaptic connection, tumour cells can trigger Ca²⁺ influx that promote proliferation and metastasis (Article). Biologically, this may mean tumor cells hijack the neural habitat to exploit synaptic plasticity, trophic support, and electrical activity.

What are the therapeutic options?

Cutting down the synaptic connection between the neuron and the cancer cell would be the best therapeutic outcome. There is support for this claim. Glutamate receptor blockade by medications showed a reduction in metastatic cell numbers in brain cancer models (Article). The other ways to block cancer cells from colonizing the brain are to target the adhesion molecules to stop neuron-cancer contact. However, the global blockade of essential receptors or adhesion molecules can also harm regular physiological function and may invoke psychological complications in patients already suffering from cancer symptoms. Unfortunately, targeted blockade specific to only cancerous cells is still a long way from being achieved. 

What does the future hold?

Possibly the most challenging question to tackle right now is to understand how synapse formation shapes typical cancer behaviors such as invasion, resistance to therapy, and immune evasion. Conversely, we need to know if these synaptic connections change neuronal function. The researchers also need to know the timing of synapse formation and the fraction of metastatic cells that engage in these synapses. It is also important to answer whether certain cancers form synaptic connections more frequently than others. In terms of therapy, we need to find ways to selectively target tumor-facilitated synapses without damaging healthy synapses. Advanced imaging or live staining techniques should be developed to specifically detect tumor-facilitated synapses so that therapy can be specifically directed to the location where most of the abnormal synaptic connections exist.

The discovery that metastatic cancer cells can form synapse-like connections with neurons reshapes our view of metastasis. It suggests these cells can blend into new tissues by tapping into local communication networks. Understanding and disrupting these neuron–tumor interfaces could offer new strategies for targeting metastatic cells across diverse physiological systems.

Header Image Source: from scienmag.com

Edited by Madison Ward, PhD

References

1. Zeng, Q., Michael, I.P., Zhang, P. et al. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature 573, 526–531 (2019). https://doi.org/10.1038/s41586-019-1576-6
2. Venkataramani, V., Tanev, D.I., Strahle, C. et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 573, 532–538 (2019). https://doi.org/10.1038/s41586-019-1564-x
3. Savchuk, S., Gentry, K.M., Wang, W. et al. Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis. Nature 646, 1232–1242 (2025). https://doi.org/10.1038/s41586-025-09492-z
4. Krutika Deshpande, Vahan Martirosian, Brooke Naomi Nakamura, Mukund Iyer, Alex Julian, Rachel Eisenbarth, Ling Shao, Frank Attenello, Josh Neman, Neuronal exposure induces neurotransmitter signaling and synaptic mediators in tumors early in brain metastasis, Neuro-Oncology, Volume 24, Issue 6, June 2022, Pages 914–924, https://doi.org/10.1093/neuonc/noab290