Using a newly developed method, researchers have succeeded for the first time in molecularly examining the nerve cells in both healthy tissue and pancreatic cancer in mice – paving the way for a potential new treatment option in the future.
Pancreatic cancer is fuelled by connections to the nervous system. In a new study, researchers have discovered that the tumour specifically reprograms the neurons for its own benefit, and that, in mice, blocking nerve function inhibited cancer growth and increased the sensitivity of tumour cells to certain chemotherapies and immunotherapies.
For several years, scientists have been discovering interactions with the nervous system in almost all types of cancer studied, interactions that in many cases promote tumour growth and survival.
This also applies to pancreatic cancer, which is interwoven with a dense network of nerves. However, only the nerve fibres project into the tumour, while the nuclei of the nerve cells lie far outside, in the ganglia, the control centres of the peripheral nervous system. Therefore, it was previously unclear which molecular interactions they enter into with cancer cells.
Pancreatic cancer reprogrammes nerve cells
Through the detailed molecular analysis of the individual neurons in the tumour, the researchers discovered that pancreatic cancer reprogrammes the gene activity of the nerves for its own benefit.
The activity of many genes is increased or attenuated, resulting in a tumour-specific signature.
What is more, even after surgical removal of the primary tumour, the tumour nervous system retained its cancer-promoting properties: when the scientists reimplanted pancreatic cancer cells into the animals that had undergone surgery, the resulting secondary tumours were twice as large as those of mice that had been transplanted with pancreatic cancer cells for the first time.
In addition to their direct interaction with cancer cells, nerve cells influence in particular the fibroblasts of the tumour (CAF – cancer-associated fibroblasts), which make up a large part of the tumour mass.
They are also stimulated to grow and contribute significantly to the suppression of the immune defence in the tumour environment.
Nerves cut – tumours shrink
When the sympathetic nerve connections to the pancreas were surgically severed or destroyed with special neurotoxins, tumour growth was significantly inhibited.
At the same time, the activity of growth-promoting genes in the cancer cells as well as in the CAFs decreased. In the CAFs, the researchers observed a significant increase in pro-inflammatory gene activity after the nerves were destroyed.
“Apparently, the neuronal connections in pancreatic cancer suppress the pro-inflammatory activity of the fibroblasts, thereby inhibiting the cancer defense by immune cells,” explains Vera Thiel, first author of the paper.
If the interruption of nerve connections apparently has an inflammatory effect, i.e. activates the immune system, this could increase the effectiveness of an immunotherapy with so-called checkpoint inhibitors (ICI).
Drugs in this group metaphorically speaking release the “brakes” of the immune system. However, they cannot combat pancreatic carcinomas on their own: the tumours are considered immunologically “cold”, meaning the therapeutically important T-cells simply cannot reach the tumour.
When the researchers blocked the neural connection to the pancreatic tumour in a mouse model using a targeted neurotoxin, the tumour became sensitive to the checkpoint inhibitor nivolumab again and the tumour mass shrank to one-sixth of the mass in control animals.
“By blocking the nerves, were able to convert an immunologically cold tumour into one that was sensitive to immunotherapy,” said Simon Renders, also first author of the publication.
Severed nerves plus chemotherapy: synergistic effect
The drug nab-paclitaxel is a component of standard chemotherapy for pancreatic cancer. In addition to inhibiting cell division, it also affects sensory nerves, which is why peripheral neuropathy is one of the known severe side effects of this agent.
Trumpp’s team showed that under repeated cycles of nab-paclitaxel, the sensory nerve fibres in the tumour decreased drastically. The tumour mass also decreased as expected.
The effect on sensory nerves apparently seems to be part of the drug’s effectiveness against pancreatic cancer. However, the remaining nerve fibres retained their cancer-promoting gene activity even under treatment.
But what happens when the tumour is completely cut off from its neuronal connections? The researchers achieved this by treating the mice with nab-paclitaxel (to block sensory nerves) and a neurotoxin to switch off the sympathetic neurons. This combination had a synergistic effect and reduced the tumour mass by more than 90 percent.
“The result underscores that both types of nerve cells have functional relevance for tumour growth,” said Vera Thiel.
”Complete blockade of the communication between nerves and tumour in combination with chemotherapy and/or immune checkpoint inhibitors is a promising approach for combating pancreatic cancer more effectively in the future.
“For example, it is conceivable to reduce the size of the tumours to such an extent that they subsequently become resectable,” Trumpp said.
His team, together with doctors from Heidelberg University Hospital, is already planning early clinical trials to test this strategy in pancreatic cancer patients.
