Peripheral nerves may inhibit melanoma growth

Nerves (in green) within a melanoma tumour. Photo by: Dr. David J. Simon

Nerve fibres within melanomas can slow tumour growth, according to a study led by Weill Cornell Medicine investigators. The findings help clarify the emerging field of cancer neuroscience and may inform future therapeutic strategies.

In the study, published April 29 in Neuron, the researchers used mouse models of melanoma to examine the presence and the effects of peripheral nerves that grow into tumours. They found that nerves of the sympathetic nervous system are often abundant in such tumours, and can inhibit tumour growth by reducing local tumour-supportive macrophages.

“The nervous system typically has been considered as a driver of cancer growth, but here we’ve found that it can be a brake on cancer growth in some contexts,” said study senior author Dr. David J. Simon, in a press release from Weill Cornell Medicine. “Now the key will be to see how broadly relevant this is for human cancers, and how we can best step on that brake to help cancer patients.”

Dr. Simon is an assistant professor of biochemistry and biophysics and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell.

In the release, the investigators note that peripheral nerves are commonly found in tumours, but only in recent years have researchers begun examining their roles in cancer outcomes. Most of these investigations have found that sensory and sympathetic nerves can enhance tumour growth, for example, by releasing molecules that suppress antitumor immunity. In just the last few years, however, there have been hints that peripheral nerves in some cases may be able to slow tumour growth instead.

Dr. Simon and his team have expertise in studying the growth and survival of peripheral nerve fibres, especially those that grow into the skin. “We knew that these nerves entered melanoma, but studying their role in cancer growth was not our main goal,” said Dr. Simon. “But we were fortunate to receive generous early-stage support from the Pershing Square Sohn Cancer Research Alliance that allowed us to take a risk and explore these nerve-tumour interactions in detail.”

“We used a technique called whole mount immuno-labelling, in which an entire tissue sample is made optically transparent, to count, identify and trace the paths of the nerves in the tumours,” said study first author Dr. Tingting Liu, a postdoctoral research associate in the David J. Simon Lab.

These initial investigations revealed that pain-sensitive nerves and sympathetic nerves were prevalent in the melanomas, increasing in number as the tumours grew, particularly in slower-growing tumours. The pain-sensitive nerves, consistent with prior studies, appeared to have a pro-tumour effect—depleting them inhibited tumour growth—but the sympathetic nerves surprisingly exerted an anti-tumour effect.

The sympathetic nerves identified in the study release norepinephrine, which can activate adrenergic receptors on nearby cells. The researchers traced the anti-tumour effect in their models to a subset of adrenergic receptors called alpha adrenergic receptors. They identified macrophages as the key cellular targets of this alpha adrenergic signalling. Tumours often switch macrophages into an immunosuppressive mode, but the alpha adrenergic signalling reduced the numbers of such pro-tumour macrophages, thereby slowing tumour growth.

The researchers say their findings open the prospect of future anti-cancer therapies that target sympathetic nerves within tumours, or even the alpha adrenergic receptors on tumour-associated macrophages. Medications targeting these receptors are already in use as common blood pressure medicines. For now, Dr. Simon plans to continue with more fundamental research, including how adrenergic receptors are activated and signal in human cancers.

“There’s a lot still to do in terms of the basic biology here,” he said.