What Role Does Sympathetic Nerve-CAF Crosstalk Play in PDAC Progression?

Sympathetic signaling enhances cancer-associated fibroblast (CAF) activation and extracellular matrix remodeling, according to research published in JCI Insight.¹ In that paper, the study investigators stated that these findings establish CAFs as central mediators of the role that sympathetic nerves play in supporting the tumor microenvironment in pancreatic 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, as well as the final study author, about the bidirectional signaling loop identified between nerves and the stroma in pancreatic ductal adenocarcinoma (PDAC). The highlights from that conversation are gathered here.

CancerNetwork: What was the rationale for evaluating the bidirectional crosstalk between sympathetic nerves and CAFs in PDAC?

Eksi: When a tumor develops in the pancreas, it triggers a wound-healing response in the surrounding supportive cells of the tissue. In many cancers, that wound-healing program never fully resolves and instead becomes part of what drives tumor progression. Simultaneously, our nervous systems continuously monitor our organs; they sense changes in tissue states and communicate those signals back to the brain. We became interested in whether nerves sense the wound-healing environment that forms in pancreatic tumors and if they actively participate in shaping that response. To answer that, we focused on CAFs because they are the key cells responsible for driving this wound-like tissue remodeling in pancreatic tumors.

How was this trial designed? Why were human samples mixed with a mouse model and nerve CAF co-cultures?

We approached this question from several complementary angles because each model answers a different part of the problem. The CAF/nerve co-culture experiments allowed us to study the mechanism more directly. We investigated how nerves and fibroblasts communicate with each other and identified the transcriptional changes that occur during this bidirectional interaction. The mouse model allowed us to test causality; by selectively ablating sympathetic nerves, we could determine whether these nerves are required for the fibroblast responses and how they affect tumor growth in vivo. The human samples were essential for connecting these findings back to patients. They allowed us to confirm that the nerve-fibroblast interactions we identified experimentally are also present in human tumors.

What was the primary finding?

We found that sympathetic nerves—those involved in the body’s sympathetic stress response—actively signal to CAFs that surround pancreatic tumors and drive them into a state that promotes tumor progression or aggression. When these fibroblasts are activated by these nerve signals, they begin remodeling the extracellular matrix around the tumor, which effectively reshapes the tissue environment in ways that support aggressive tumor growth. Interestingly, we found the communication [is bidirectional]; signals from the fibroblasts trigger a response in the sympathetic nerves that resembles a nerve injury response. This activates a transcriptional program that has been linked in other recent studies to immunosuppression in tumors. Together, our findings reveal a bidirectional signaling loop between sympathetic nerves and fibroblasts that reorganizes the tumor microenvironment.

What is the significance of these findings?

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

What did the study find in relation to exposure to PSC-derived CAFs and the transcriptional response to nerve injury?

This was a very important layer to our understanding of how nerves shape the tumor microenvironment. A paper published in Nature by the groups of Moran Amit, MD, PhD, and Sebastien Talbot, PhD, a few months ago showed that nerves can acquire a damage response when innervating a tumor.² This response activates an inflammatory repair program that can suppress antitumor immunity through the PD-1/PD-L1 axis, which contributes to resistance to immunotherapy in multiple different tumor types. Our work complements this by showing that nerves can also directly reprogram fibroblasts in the stroma, driving tissue remodeling that supports tumor growth.

Denervation significantly reduced tumor size in female mice, but not in male mice. What biological or hormonal drivers do you think are responsible for this difference in neural tumor-support?

This was one of the most unexpected findings of the study and something we are continuing to investigate. The nervous system is closely connected to the body’s hormonal and neuroendocrine systems, and we know that these signals can influence both nerve activity and the surrounding tumor microenvironment. Our results suggest that the way sympathetic nerves support tumor growth may be different between males and females. At this stage, we do not yet know the precise biological mechanism driving this difference, but it is interesting that the sympathetic nervous system may have a sex-dependent effect on tumors, which has not been widely explored in cancer neuroscience.

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

When sympathetic signals act on these fibroblasts, they appear to shift into a more inflammatory CAF state, or iCAFs, which we also detected through cytokine profiling assays. In this state, the fibroblasts interact differently with collagen and the surrounding matrix, 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 has been shown in previous studies to induce epithelial-to-mesenchymal transition states in pancreatic tumor cells.

What future research can build off these findings?

One important next step for us is to better understand how sympathetic signaling reshapes the broader tumor microenvironment. My lab utilizes spatial profiling; we develop experimental and computational tools to map nerves in patient samples and look at the systems-level changes that happen around nerves in fibroblasts, immune cells, and tumor cells. This is essential for validating the signaling pathways that we identified in experimental models and human samples. Another longer-term goal is to explore whether targeting these signaling pathways in sympathetic nerves in the tumor microenvironment could become part of combinatorial therapeutic strategies to slow pancreatic tumor progression.

Are you working on any other research you want to highlight?

We have 2 papers in the pipeline focused on the systems-level understanding of how nerves are integrated into the tumor microenvironment. Until now, studying tumor innervation at scale has been extremely difficult because these nerve fibers are small, heterogeneous, and challenging to identify in microscopic images. We recently developed a computational tool called AxonFinder, which allows us to automatically segment and quantify very fine nerve fibers in patient samples. Using this approach, we are now generating high-resolution spatial maps of tumor innervation in human cancers. We have an upcoming study where we apply AxonFinder to large cohorts of patients to understand how these nerve fibers are organized within tumors and how they are interacting with the surrounding stromal and immune cells.

References

1. 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
2. Baruch EN, Gleber-Netto FO, Nagarajan P, et al. Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy. Nature. 2025;646(8084):462-473. doi:10.1038/s41586-025-09370-8