Scientists expose neurons hindering cancer treatment

For some time now, scientists have been aware of interactions between tumors and the nervous system in nearly every type of cancer studied. These interactions in many cases promote tumor growth and survival, including in pancreatic cancer, which is interwoven with a dense network of nerves, but a new discovery brings hope.

Recently, scientists from the German Cancer Research Center (DKFZ) and the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) have discovered that pancreatic cancer specifically reprograms neurons for its own benefit, as they reported in Nature on February 18.

By blocking the nerve function in mice, these experts managed to suppress cancer growth and enhance the sensitivity of tumor cells to certain chemotherapies and immunotherapies, but until now they couldn’t discern which molecular interactions the ganglia (the control centers of the peripheral nervous system) enter into with cancer cells.

However, the team under the leadership of Andreas Trumpp has finally succeeded in molecularly examining the nerve cells in both healthy tissue and pancreatic cancer in mice, providing a detailed molecular analysis of the individual neurons in the tumor with reprogramed gene activity.

Increasing effectiveness of immunotherapy

When the scientists surgically severed or destroyed with special neurotoxins the sympathetic nerve connections to the pancreas, tumor growth significantly decelerated, the growth-promoting genes in the cancer cells and cancer-associated fibroblasts (CAFs) decreased, and pro-inflammatory gene activity substantially increased.

With the inflammatory effect or the nerve connection interruption, the immune system activates, which could increase the effectiveness of immunotherapy with so-called checkpoint inhibitors (ICIs). They release the “brakes” of the immune system but cannot combat pancreatic carcinomas alone, as the tumors are immunologically “cold,” which means the therapeutically important T-cells cannot reach the tumor.

Once the researchers blocked the neural connection to the pancreatic tumor in a mouse model using a targeted neurotoxin, the tumor became sensitive to the ICI nivolumab again and the tumor mass actually shrank to one-sixth of the mass in control animals.

Summarizing the team’s results, Simon Renders, one of the publication’s authors, explained:

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

Synergistic effect with chemotherapy

Meanwhile, completely cutting off the tumor’s neuronal connections using the drug nab-paclitaxel (a component of standard chemotherapy for pancreatic cancer) and a neurotoxin to switch off the sympathetic neurons reduced the tumor mass by more than 90%!

Notably, nab-paclitaxel inhibits cell division but also affects sensory nerves, which is why peripheral neuropathy is one of its more severe side effects. Under repeated cycles of the drug, the sensory nerve fibers in the tumors decreased drastically but retained their cancer-promoting gene – until a neurotoxin came into play – with exceptional results.

Vera Thiel, the first author of the paper, commented that:

“The result underscores that both types of nerve cells have functional relevance for tumor growth. (…) Complete blockade of the communication between nerves and tumor 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 tumors to such an extent that they subsequently become resectable.”

All things considered, this is a significant breakthrough in the never-ending struggle to defeat cancer, which kills millions of people every year and has a major impact on society in the United States and across the world. As such, it signals the possibility of a sleuth of promising solutions in cancer treatment.