Pancreatic cancer is one of the deadliest types of tumours. A team at the Technical University of Munich (TUM) has discovered that pancreatic tumours exploit the body’s nervous system by forming so-called pseudosynapses. Through a specific receptor, the cancer cells take up the neurotransmitter glutamate, which drives tumour growth. The researchers now hope to identify drugs that can block this process in patients.
It has been known for some time that the nervous system can affect cancer development. For example, nerve cells from healthy tissue can grow into tumors, a phenomenon known as “neural invasion,” which is typically linked to a poor prognosis.
About six years ago, a US research group discovered a new mechanism in the brain: tumours can form their own synapses, co-opting neuronal communication for their benefit. Professor Ekin Demir, a clinician scientist at the Department of Surgery at the TUM University Hospital, and his team built on this finding to investigate whether tumours outside the brain might form similar structures.
Searching for “tumour synapses”
Pancreatic tumours often show neural invasion. Thus, if such synapse-like structures existed outside the brain, this was the most likely place to find them. The researchers searched pancreatic tumour tissue for clusters of receptors specialised for specific neurotransmitters. In some samples, they did indeed find a strong concentration of NMDA receptors – the receptors that bind glutamate. Then came the successful search for the characteristic structures of synapses, carried out in the classic way under the electron microscope Owing to subtle physiological differences compared with typical neuronal synapses, the researchers refer to these structures as pseudosynapses.
Calcium waves promote tumour growth
What advantage do pancreatic tumours gain by forming pseudosynapses? Like other glands, the pancreas is regulated by the nervous system. Depending on the body’s needs healthy pancreatic cells receive the neurotransmitter glutamate through their synapses. This triggers a series of processes. Pseudosynapses exploit this natural mechanism. “When glutamate binds to the cancer cells’ NMDA receptors, a channel opens and calcium flows into the cell,” explains Professor Demir. “This influx triggers molecular signalling cascades that drive tumour growth and metastasis.” The team observed that the cancer cells generate characteristic slow, long-lasting calcium waves that drive tumour growth in a sustained way.
Yet this remarkable mechanism may open up a path to new cancer therapies. In mouse experiments, the researchers successfully blocked the NMDA receptors on tumour cells with a drug. The result: pancreatic tumours grew more slowly, developed fewer metastases, and the animals lived longer.
“We are currently using bioinformatic methods to identify approved drugs that, in addition to their primary effects, can also block these specific NMDA receptors in pancreatic cancer cells,” says Professor Ekin Demir. “Therapies targeting the interface between the nervous system and tumours could open up entirely new treatment options.” The team suspects that other tumour types may also form pseudosynapses to accelerate their growth.
The study is published in Cancer Cell.
Source: Technical University of Munich
