Sympathetic Nerves Signal to CAFs and Promote Pancreatic Tumor Aggression

Sympathetic nerves actively signal to cancer-associated fibroblasts (CAFs) within the pancreatic tumor microenvironment, inducing a state that promotes tumor aggression. According to Sebnem Ece Eksi, PhD, and colleagues, these nerves which are integral to the body’s sympathetic stress response facilitate a strategic remodeling of the extracellular matrix. This structural reorganization effectively reshapes the tissue environment in ways that support aggressive tumor growth in patients with pancreatic cancer. By driving CAFs into this activated state, the nervous system participates directly in the physical and biochemical evolution of the tumor site.

Following the publication of this study, CancerNetwork® spoke with Eksi, an assistant professor in the Division of Oncological Sciences in the School of Medicine and at CEDAR in the Oregon Health and Science University Knight Cancer Institute, and an investigator on the trial, about the key takeaways from the study.

The research further illuminated a complex bidirectional signaling loop between the neural and stromal components of the tumor microenvironment. While sympathetic nerves influence CAF activity, signals originating from the fibroblasts simultaneously trigger a response in the nerves that mirrors a nerve injury response. This interaction activates a specific transcriptional program within the sympathetic nerves.

Together, these findings revealed that the relationship between sympathetic nerves and fibroblasts is not a unidirectional influence but a continuous, reciprocal communication that reorganizes the tumor microenvironment. Deciphering the molecular language shared between these 2 cell types presents a significant opportunity for the identification of novel therapeutic targets.

A primary finding of this study was the identification of the semaphorin 3C/neuropilin 1 axis as a specific molecular pathway. Targeting this axis may provide a new avenue for therapeutic strategies designed to interfere with the bidirectional signaling that supports pancreatic tumor aggression.

Transcript:

What was the primary finding of this study?

In this study, we found that sympathetic nerves—these are the nerves involved in our body’s fight or flight response as the stress response—actively signal to CAFs that surround the pancreatic tumors and drive them into a state that promotes tumor aggression. When these fibroblasts are activated by these nerve signals, they begin remodeling the extracellular metrics around the tumor, and this effectively reshapes the tissue environment in ways that supports aggressive tumor growth. What’s interesting is that we found, at the same time, the communication goes both ways; signals from the fibroblasts then trigger what looks like a nerve injury response in the sympathetic nerves and activates a transcriptional program that has been linked in other recent studies to immunosuppression in tumors. Together, our findings reveal that there is a bidirectional signaling loop between sympathetic nerves and fibroblasts that reorganizes the tumor microenvironment.

Understanding the molecular language that is used between nerves and CAFs allows us to identify new ligand receptor pairs that can be then used as therapeutic targets. In our specific study, we identified semaphorin 3C/neuropilin 1 as one of these molecular axes that can be further targeted.

References

Sattler AL, Diba P, Hawthorne K, et al. Sympathetic nerve–fibroblast crosstalk drives nerve injury, fibroblast activation, and matrix remodeling in pancreatic cancer. JCI Insight. Published February 19, 2026. doi:10.1172/jci.insight.192814