Author
Listed:
- Vera Thiel
(Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
Heidelberg University)
- Simon Renders
(Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
Heidelberg University Hospital
DKFZ)
- Jasper Panten
(Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
Heidelberg University)
- Nicolas Dross
(University of Heidelberg)
- Katharina Bauer
(DKFZ)
- Daniel Azorin
(Heidelberg University
German Cancer Research Center (DKFZ))
- Vanessa Henriques
(Heidelberg University Hospital)
- Vanessa Vogel
(Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Heidelberg University Hospital)
- Corinna Klein
(Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance)
- Aino-Maija Leppä
(Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
Heidelberg University)
- Isabel Barriuso Ortega
(Heidelberg University
German Cancer Research Center (DKFZ))
- Jonas Schwickert
(Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
Heidelberg University)
- Iordanis Ourailidis
(Heidelberg University Hospital)
- Julian Mochayedi
(Heidelberg University
German Cancer Research Center (DKFZ))
- Jan-Philipp Mallm
(DKFZ)
- Carsten Müller-Tidow
(Heidelberg University Hospital
DKFZ)
- 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)
Heidelberg University Hospital)
- Martin Sprick
(Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance)
- Andreas Trumpp
(Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance
DKFZ)
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.
Suggested Citation
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 Sch, 2025.
"Characterization of single neurons reprogrammed by pancreatic cancer,"
Nature, Nature, vol. 640(8060), pages 1042-1051, April.
Handle:
RePEc:nat:nature:v:640:y:2025:i:8060:d:10.1038_s41586-025-08735-3
DOI: 10.1038/s41586-025-08735-3
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