Characterization of single neurons reprogrammed by pancreatic cancer

Vera Thiel, Simon Renders, Jasper Panten, Nicolas Dross, Katharina Bauer, Daniel Azorin, Vanessa Henriques, Vanessa Vogel, Corinna Klein, Aino-Maija Leppä, Isabel Barriuso Ortega, Jonas Schwickert, Iordanis Ourailidis, Julian Mochayedi, Jan-Philipp Mallm, Carsten Müller-Tidow, Hannah Monyer, John Neoptolemos, Thilo Hackert, Oliver Stegle, Duncan T. Odom, Rienk Offringa, Albrecht Stenzinger, Frank Winkler, Martin Sprick and Andreas Trumpp ()
Additional contact information
Vera Thiel: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Simon Renders: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Jasper Panten: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Nicolas Dross: University of Heidelberg
Katharina Bauer: DKFZ
Daniel Azorin: Heidelberg University
Vanessa Henriques: Heidelberg University Hospital
Vanessa Vogel: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Corinna Klein: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Aino-Maija Leppä: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Isabel Barriuso Ortega: Heidelberg University
Jonas Schwickert: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Iordanis Ourailidis: Heidelberg University Hospital
Julian Mochayedi: Heidelberg University
Jan-Philipp Mallm: DKFZ
Carsten Müller-Tidow: Heidelberg University Hospital
Hannah Monyer: German Cancer Research Center (DKFZ)
John Neoptolemos: Heidelberg University Hospital
Thilo Hackert: Heidelberg University Hospital
Oliver Stegle: German Cancer Research Center (DKFZ)
Duncan T. Odom: German Cancer Research Center (DKFZ)
Rienk Offringa: German Cancer Research Center (DKFZ)
Albrecht Stenzinger: Heidelberg University Hospital
Frank Winkler: German Cancer Research Center (DKFZ)
Martin Sprick: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Andreas Trumpp: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)

Nature, 2025, vol. 640, issue 8060, 1042-1051

Abstract: Abstract The peripheral nervous system (PNS) orchestrates organ function in health and disease. Most cancers, including pancreatic ductal adenocarcinoma (PDAC), are infiltrated by PNS neurons, and this contributes to the complex tumour microenvironment (TME)1,2. However, neuronal cell bodies reside in various PNS ganglia, far from the tumour mass. Thus, cancer-innervating or healthy-organ-innervating neurons are lacking in current tissue-sequencing datasets. To molecularly characterize pancreas- and PDAC-innervating neurons at single-cell resolution, we developed Trace-n-Seq. This method uses retrograde tracing of axons from tissues to their respective ganglia, followed by single-cell isolation and transcriptomic analysis. By characterizing more than 5,000 individual sympathetic and sensory neurons, with about 4,000 innervating PDAC or healthy pancreas, we reveal novel neuronal cell types and molecular networks that are distinct to the pancreas, pancreatitis, PDAC or melanoma metastasis. We integrate single-cell datasets of innervating neurons and the TME to establish a neuron–cancer–microenvironment interactome, delineate cancer-driven neuronal reprogramming and generate a pancreatic-cancer nerve signature. Pharmacological denervation induces a pro-inflammatory TME and increases the effectiveness of immune-checkpoint inhibitors. The taxane nab-paclitaxel causes intratumoral neuropathy, which attenuates PDAC growth and, in combination with sympathetic denervation, results in synergistic tumour regression. Our multi-dimensional data provide insights into the networks and functions of PDAC-innervating neurons, and support the inclusion of denervation in future therapies.

Date: 2025
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DOI: 10.1038/s41586-025-08735-3

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