Link between sensory neurons and breast cancer metastasis discovered

Now, in the new paper Nature Activation of sensory nerves within breast cancer tumors appears to play a key role in promoting not only cancer growth but also its spread, a process known as metastasis. The discovery that sensory neurons secrete neuropeptides to promote cancer growth and spread through a previously unknown nerve-cancer interaction suggests that targeting this pathway may halt breast cancer progression. The study also found that an FDA-approved drug commonly used to treat nausea may prevent metastasis in these cases.

“Neuron hyperactivation has been observed in tumors growing in the brain, but this is the first time we've seen it in epithelial tumors such as breast cancer,” said Veena Padmanabhan, a postdoctoral researcher in Sohail Tavazoi's lab and lead author of the study. “This is an exciting discovery. No one has ever seen peripheral nerves send out signals that promote metastasis before.”

irritating to cancer patients

Scientists have long known that there is a connection between cancer cells and the nervous system. Solid tumors secrete proteins that recruit nerves to the primary tumor site. Neuronal markers have been detected in cancers of the head and neck, breast, cervical, esophagus, colon and pancreas, and studies suggest that autonomic nervous system nerves that control involuntary processes such as heart rate and blood pressure may drive the progression of prostate and stomach tumors.

Whether the nervous system could facilitate the metastatic progression of breast cancer, the world's most common cancer, remained a mystery, but it seemed plausible: healthy breast tissue is rich in sensory nerves, and there was evidence of innervation of breast cancer in the literature.

“We had evidence that innervation was associated with worse outcomes in breast cancer,” says Tavazoy, the Leon Hess Professor at Rockefeller University, “and then we finally looked at breast cancer tumors and found that the more metastatic tumors had much more sensory innervation.”

With this observation in mind, the team used mouse models to compare the innervation of highly metastatic and less metastatic tumors. They then ablated sensory nerves within breast tumors by culturing cancer cells with sensory neurons to examine the effects on breast cancer cells in vitro and analyzed published data to correlate neural markers with metastatic recurrence in breast cancer patients.

The results demonstrated that innervation induces metastasis. “We now know that nerves not only promote the growth of breast cancer cells, but also help the cells metastasize and invade tissues,” Tavazoy says. This alone was an important finding, because metastatic disease plays a disproportionate role in cancer outcomes. “Metastasis is the leading cause of death for most cancers. Patients die because the cancer spreads to distant organs,” Padmanabhan says. “Finding ways to stop metastatic disease is one of the greatest biomedical challenges of our time.”

Nerve-cancer axis

As the team probed deeper, a more complete picture emerged. The researchers found that the enhanced innervation observed in malignant tumors is driven by expression of the SLIT2 gene in the tumor vasculature. This gene codes for a protein that guides the growth of axons to establish neural connections. They found that when nerves enter the tumor, they begin to secrete a neuropeptide called substance P, which interacts with the cancer cell receptor TACR1 to promote tumor growth and metastasis. They also found that this interaction causes some cancer cells to die, releasing single-stranded RNA that binds to an RNA-sensing receptor on the cancer cells and activates metastasis-promoting genes, propelling the remaining cells forward.

“It has been reported that nerves can physically interact with and directly affect certain cancer cells, but we have observed a neuropeptide signaling mechanism in which nerves release neurotransmitter signals that spread to breast cancer cells,” Padmanabhan says. “We also see that neuropeptides can act directly on cancer cells to activate an RNA signaling response, which releases single-stranded RNA that can act on nearby cells to activate a set of genes. This was unexpected and may have relevance beyond cancer.”

The findings have significant clinical implications: Published data show that elevated levels of a metastasis-promoting neuropeptide and a gene signature associated with this neuropeptide and ssRNA are both associated with increased metastasis and decreased survival in breast cancer patients. The team also successfully blocked growth and metastasis in multiple breast cancer models when they treated mice with aprepitant, an FDA-approved TACR1 antagonist that is typically administered to patients undergoing chemotherapy to prevent nausea.

“Because aprepitant is already approved and safe, oncologists may consider clinical trials to study the drug's effect on cancer progression in patients with breast cancer,” Tavazoi said.

Even if aprepitant is not the most effective treatment, the study gives researchers a new therapeutic target and paves the way for targeted therapies. “Our study may help bridge the gap between the fields of cancer metastasis biology and neuroscience, encouraging cancer biologists and neuroscientists to work together and bring together the tools of their respective fields.”