Pancreatic cancer: nerve cutting as a new treatment strategy

Pancreatic cancer feeds through connections with the nervous system. Scientists from the German Cancer Research Center (DKFZ) and the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) report this in the journal Nature.

The team found that the tumor specifically reprograms neurons for its own purposes. In mice, blocking nerve function suppressed cancer growth and made tumor cells more sensitive to certain chemotherapy and immunotherapy drugs.

For several years, scientists have been finding interactions with the nervous system in virtually every type of cancer studied – interactions that in many cases promote tumor growth and survival. This includes pancreatic cancer, which is intertwined with a dense network of nerves.

However, only nerve fibers penetrate the tumor, and the nuclei of nerve cells are located far outside the tumor, in the ganglia, the control centers of the peripheral nervous system. Therefore, it was previously unclear what molecular interactions these cells enter into with cancer cells.

Using a newly developed method, a team led by Andreas Trumpp from DKFZ and HI-STEM has succeeded for the first time in performing a molecular study of nerve cells in both healthy tissue and pancreatic cancer tissue in mice.

Pancreatic cancer reprograms nerve cells

In pancreatic tumors, nerves are extremely well branched and are in contact with most tumor cells. Through detailed molecular analysis of individual neurons in the tumor, the researchers found that pancreatic cancer reprograms the activity of genes in the nerves to its advantage. The activity of many genes is enhanced or weakened, resulting in tumor-specific features.

Moreover, even after surgical removal of the primary tumor, the tumor nervous system continued to retain its cancer-promoting properties: when scientists re-transplanted pancreatic cancer cells into animals that had undergone surgery, the secondary tumors that formed were twice as large as those in mice to which pancreatic cancer cells had been transplanted the first time.

In addition to interacting directly with cancer cells, nerve cells affect, among other things, tumor fibroblasts, which make up the majority of the tumor mass. They also undergo growth stimulation and contribute significantly to the suppression of immune defenses in the tumor environment.

Cutting nerves shrinks tumors

When sympathetic nerve connections to the pancreas were surgically severed or destroyed using special neurotoxins, tumor growth was significantly slowed down. At the same time, the activity of growth-promoting genes in both cancer cells and fiyuroblasts decreased. The researchers observed a significant increase in the activity of pro-inflammatory genes in the fibroblasts after nerve destruction.

“It appears that neural connections in pancreatic cancer suppress the pro-inflammatory activity of fibroblasts, thereby preventing immune cells from protecting the cancer,” explains Vera Thiel, first author of the paper.

Transected nerves improve the efficacy of immunotherapy

If the cutting of nerve connections apparently has an inflammatory effect, i.e. activates the immune system, this may increase the effectiveness of immunotherapy with so-called checkpoint inhibitors (ICTs). Drugs of this group, figuratively speaking, release the “brakes” of the immune system.

However, they cannot fight pancreatic carcinomas on their own: tumors are considered immunologically “cold”, i.e. therapeutically important T cells simply cannot reach the tumor.

When the researchers blocked neural connections to a pancreatic tumor in a mouse model using a targeted neurotoxin, the tumor became sensitive again to the checkpoint inhibitor nivolumab, and its mass decreased to one-sixth that of control animals.

“By blocking nerves, we were able to turn an immunologically cold tumor into one that was sensitive to immunotherapy,” the researchers report.

The severed nerves combined with chemotherapy have a synergistic effect

Severance Gangnam Hospital Republic of Korea,SeoulLeave a request

Schneider Children's Medical Center Israel,Petah TikvaLeave a request

Published: 19.02.2025

Updated: 18.02.2025

Medical author, Medical editor:

Stepan Yuk

Medical expert:

PhD. Olexandr Voznyak