GoKawiilNeurons (magenta) innervate a small cell lung cancer tumour.Credit: Rachel Davis, Venkatesh Lab
At first, Filippo Beleggia had no interest in neurons. A cancer biologist studying small-cell lung cancer (SCLC), he deployed a sophisticated screening technique to search for genes that drive tumour progression in a mouse model of the disease. Although it accounts for only around 15% of lung cancers, SCLC is the most aggressive and metastatic form of the disease and has limited options for treatment. Beleggia was hoping to identify genes involved in processes such as cell division or responses to DNA damage, and says his aim was to discover genes “that we could then build therapies on”.
What this first screen delivered, however, was a list of genes implicated in neurobiology. Such was the surprise, Beleggia says, that his team dismissed it as an artefact of the technique they had used.
Nature Outlook: Lung cancer
It was known that a high fraction of cells in SCLC tumours resemble neuroendocrine cells — with the lung’s native neuroendocrine cells being the suspected origin of these tumours. Given that such cells release hormones or neurotransmitters and express a handful of neuronal markers. Beleggia saw the result as a “by-product of this neuroendocrine differentiation”, adding that the phenomenon “doesn’t really have any relevance for the cancer state”.
He and his colleagues at the University of Cologne in Germany therefore ran a second large-scale screen, then a third. One screen looked for genes that are most often mutated in human SCLC tumours. The other identified the genes most abundantly expressed in SCLC tumours compared with other cancers and in healthy tissues. The techniques were different, but the results were the same — the top hits were dominated by genes with neuronal functions.
What struck Beleggia in particular was that many of these genes were involved in the assembly and maintenance of synapses — the cell-to-cell junctions across which neurotransmitters travel to allow neurons to regulate their targets. “This was completely unexpected,” he says.
Working with neuroscientist collaborators, Beleggia showed that SCLC cells form true synapses with neurons. Their paper was published last September1, alongside a study by US researchers who had made the same discovery2.
The US study was led by Michelle Monje, a neuro-oncologist at Stanford University in California, and Humsa Venkatesh, a cancer biologist at Harvard University in Cambridge, Massachusetts, and one of Monje’s former postdocs. They had previously shown that primary brain tumours are intimately regulated by interactions with neurons. Wanting to know how common it is for cancers to be directly influenced by neurons, Venkatesh suggested that they look at cancers that metastasize to the brain. SCLC was an obvious choice. “Lung cancer actually represents the most common brain cancer,” says Monje.
The finding that neurons form synapses with SCLC cells was a surprise. But more important for the development of fresh treatments was the demonstration that synaptic input accelerates SCLC progression.
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