ABOVE: Neurocircuit formation between two macrophage-derived neuronlike cells in vitro PHILIP TANG AND PATRICK TANG

Pain is an unrelenting symptom of cancer that can upend the life of a patient. For decades, researchers have relied on opioids to provide relief while trying to find an alternative solution because of the drugs’ side effects, to little avail.

Now, researchers at the Chinese University of Hong Kong (CUHK) have uncovered a novel mechanism that, they say, could be at the center of generating cancer pain. They found that macrophages—white blood cells that are part of the body’s immune system—that have infiltrated lung tumors can begin to mimic neurons and actually sense pain. The phenomenon, which the team dubbed “macrophage to neuron-like transition” or MNT in a study published October 7 in Science Advances, offers a potential explanation as to why some cancer patients are unable to find pain relief through use of conventional painkillers, says Patrick Tang, a biochemist at CUHK and coauthor of the paper.

“A lot of neuropathic pain conditions are very difficult to treat,” says Tracey Ignatowski, a University at Buffalo pathologist who was not involved in the current work. “We’re looking for new ways to more effectively manage or alleviate pain, and [MNT] offers potentially a unique target for therapeutic potential.”

Prior research in the field found that nerve innervation, where the nervous system begins to communicate with tumor cells, plays an important role in tumor growth and cancer progression. In a bid to understand the origin of pain-sensing neurons in lung cancer, Tang and his colleagues began their study by using RNA-sequencing technology on tumor cells obtained from mice with lung cancer. That’s when they realized that the putative neurons were, in fact, neuronlike cells that also closely resembled macrophages. Other studies have suggested that macrophages can mimic many other types of cells, lending credibility to the new discovery, but how the cells performed such a transition remained a mystery.

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So the team used chromatin immunoprecipitation to analyze the genomic changes that macrophages undergo in order to pick up neural phenotypes. Based on the alterations to gene expression this technique revealed, they hypothesized that a transcription factor called SMAD3 may initiate this transition. Lo and behold, when the researchers used gene deletion and drugs to inhibit SMAD3 activity in immune-deficient mice, there were fewer neuronlike cells than in control mice, and the animals also exhibited fewer pain-driven behaviors, such as licking and flinching.

As a researcher who has been studying neuron-macrophage interaction for more than two decades, Ignatowski says she’s excited about the potential of using these findings to further her work in the field. However, she says she also questions whether these results will translate to humans and if the same mechanism occurs in other types of cancers. “Eventually, they may find out that macrophages can actually undergo this type of transition to a neuronlike phenotype in every disease in the right conditions,” she says. “So that’s something that needs to be investigated.”

Daniel Adams, a molecular biologist with the biotech company Creatv MicroTech in Maryland who wasn’t involved in the study, shares Ignatowski’s reservations. “I’m always a little hesitant about jumping to conclusions in mouse models,” he tells The Scientist. According to Adams, using immune-deficient animals to study the immune system is counterintuitive. “But you have to start somewhere,” he admits, adding the work is interesting and involves the use of many cutting-edge technologies, but how it will translate to humans remains to be seen.

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Tang and his colleagues agree that these are limitations of their work. But for them, there’s an even bigger limitation that has their focus: “When we’re detecting pain, we’re struggling how to prove the association in mice,” Tang says. For this reason, the group is now planning to conduct a study in cancer patients to better understand how their novel mechanism relates to cancer pain and whether there are ways to manage or reduce it.

“I want cancer patients to feel like they have hope,” Tang says. “Some of them are really frustrated with the pain and quality of life. And I just want them to know there is someone working on this.”