How the connection between lung cancer and the brain could lead to better treatments

A cancer biologist studying small-cell lung cancer used gene screening in a mouse model to find genes that drive tumour progression. The initial screen unexpectedly produced a list of genes linked to neurobiology, leading the team to suspect a technical artefact. Because small-cell lung cancer cells resemble neuroendocrine cells, the first results were initially treated as a by-product of neuroendocrine differentiation. Additional large-scale screens were then performed using different approaches: one focused on genes frequently mutated in human tumours, and another focused on genes highly expressed in tumours relative to other cancers and healthy tissues. Both screens produced the same neuronal-dominated gene hits, including many involved in synapse assembly and maintenance.

"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 "

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