Research Perspective: Single Neuron – Single Cell Resolution Trace-n-seq

The peripheral nervous system (PNS) coordinates organ function in health and disease. Most cancers, including pancreatic ductal adenocarcinoma (PDAC), are associated with PNS neurons, leading to a complex tumor microenvironment (TME). However, neuronal cell bodies exist in various PNS ganglia, away from tumor masses. Therefore, neurons innervating cancer or healthy organs have evaded current tissue sequencing datasets.

Today, researchers from Heidelberg University (Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) Vera Thiel, Simon Renders, Jasper Panten, Andreas Trumpp, et al.) published in Nature, developing “Trace-n-seq” to molecularly characterize neurons innervating the pancreas and PDAC at single-cell resolution. This method employs retrograde tracing from tissues to their respective ganglia, followed by single-cell isolation and transcriptomic analysis.

By characterizing over 5,000 sympathetic and sensory neurons, about 4,000 of which innervate PDAC or healthy pancreas, the study reveals new neuronal cell types and unique molecular networks distinct from those in the pancreas, pancreatitis, PDAC, or melanoma metastasis.

Single-cell datasets integrating neural innervating neurons and TME were also combined to establish a neural-cancer-microenvironment interaction map, depicting cancer-driven neuronal reprogramming and generating pancreatic cancer-neural signals. Pharmacological denervation induced a pro-inflammatory TME and increased the efficacy of immune checkpoint inhibitors. Albumin-bound paclitaxel can cause intratumoral neuropathy, thereby attenuating PDAC growth and can synergistically inhibit tumor growth when combined with denervation.

This multidimensional data indicates new insights into the networks and functions of PDAC-innervating neurons, suggesting that denervation could be considered in future therapies.

Characterization of single neurons reprogrammed by pancreatic cancer.

Characterization of single neurons reprogrammed by pancreatic cancer.

Fig 1: Characterization of pancreatic innervating neurons through Trace-N-Seq.

Fig 2: Tumor-specific neuronal expression profile induced by PDAC.

Fig 3: PDAC alters neuronal interactions and attracts specific subtypes in the TME.

Fig 4: In 672 CAFs making PDAC sensitive to immune checkpoint inhibitors, denervation slows PDAC growth and induces pro-inflammatory changes.

Fig 5: Albumin-bound paclitaxel reduces tumor growth by depleting tumor-infiltrating neurons.

Reference link

Thiel, V., Renders, S., Panten, J. et al. Characterization of single neurons reprogrammed by pancreatic cancer. Nature (2025). https://doi.org/10.1038/s41586-025-08735-3

This article is translated from Nature.

Source: Today’s New Materials

Disclaimer: Represents only the translator’s viewpoint; please leave comments below for corrections if there are scientific inaccuracies!

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