Sympathetic Signaling and Inflammatory CAF Phenotypes in Pancreatic Tumor Cells

Sympathetic signaling modulates the functional state of cancer-associated fibroblasts (CAFs) within the tumor microenvironment of pancreatic ductal adenocarcinoma, according to findings from a recent study published in JCI Insight. Investigators observed that when sympathetic signals act upon these fibroblasts, the cells undergo a transition into a more inflammatory CAF state, termed iCAFs. This phenotypic shift was further validated through cytokine profiling assays, which confirmed the presence of the inflammatory markers associated with this specific fibroblast population in patients with cancer.

CancerNetwork® spoke with Sebnem Ece Eksi, PhD, 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 the final author of this study, about these results.

The transition to an iCAF state significantly alters the interaction between fibroblasts and the surrounding extracellular matrix. Specifically, sympathetic signaling results in reduced fibroblast adherence to collagen I. This mechanical change suggests that the tissue environment becomes more permissive for tumor invasion, as the altered matrix remodeling facilitates the movement of cancer cells through the stroma. The research indicates that the interplay between neural signaling and the physical organization of the stroma is a critical factor in the progression of pancreatic cancer.

Data from mouse models support the causality of this relationship. In models where sympathetic nerves were removed, investigators observed distinct changes in collagen organization and a simultaneous shift in the states of fibroblasts within the tumor. This suggests that continuous sympathetic input is necessary to maintain the iCAF phenotype and the subsequent matrix remodeling that supports tumor development.

A key molecular driver identified in this bidirectional communication is semaphorin 3C. This signaling molecule serves as a mediator between the sympathetic nervous system and the pancreatic stroma. The study highlights that semaphorin 3C has the capacity to induce epithelial-to-mesenchymal transition (EMT) states in pancreatic tumor cells, a process that further enhances the invasive potential of the tumor. By characterizing the role of sympathetic signaling in inducing these inflammatory states and promoting EMT through semaphorin 3C, the study provides a clearer understanding of how the nervous system actively reshapes the tumor microenvironment to support the progression of disease.

Transcript:

This study found that sympathetic signaling reduced fibroblast adherence to Collagen I, which potentially increases the tumor’s invasive potential. What do these findings mean?

That was an unexpected finding. When sympathetic signals act on these fibroblasts, they appear to shift into a more inflammatory CAF states, or we call them iCAFs…which we also detected in the same iCAF phenotype through cytokine profiling assays. In this state, the fibroblasts interact differently with collagen and the surrounding metrics which may make the tissue environment more permissive for tumor invasion. Consistent with this idea, when we remove sympathetic nerves in our mouse model, we observe changes in collagen organization and a shift in fibroblast states within the tumor. We found that one of the signals involved in this communication is semaphorin 3C, which as shown in previous studies, can induce epithelial-to-mesenchymal transition states in pancreatic tumor cells.

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