TY  - JOUR
AU  - Thiel, Vera
AU  - Renders, Simon
AU  - Panten, Jasper
AU  - Dross, Nicolas
AU  - Bauer, Katharina
AU  - Azorin, Daniel
AU  - Henriques, Vanessa
AU  - Vogel, Vanessa
AU  - Klein, Corinna
AU  - Leppä, Aino-Maija
AU  - Barriuso Ortega, Isabel
AU  - Schwickert, Jonas
AU  - Ourailidis, Iordanis
AU  - Mochayedi, Julian
AU  - Mallm, Jan-Philipp
AU  - Müller-Tidow, Carsten
AU  - Monyer, Hannah
AU  - Neoptolemos, John
AU  - Hackert, Thilo
AU  - Stegle, Oliver
AU  - Odom, Duncan
AU  - Offringa, Rienk
AU  - Stenzinger, Albrecht
AU  - Winkler, Frank
AU  - Sprick, Martin
AU  - Trumpp, Andreas
TI  - Characterization of single neurons reprogrammed by pancreatic cancer.
JO  - Nature
VL  - 640
SN  - 0028-0836
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DKFZ-2025-00387
SP  - 1042–1051
PY  - 2025
N1  - #EA:A010#LA:A010# / 640, pages 1042–1051 (2025)
AB  - The peripheral nervous system (PNS) orchestrates organ function in health and disease. Most cancers including pancreatic ductal adenocarcinoma (PDAC) are infiltrated by PNS neurons, contributing to the complex tumor microenvironment (TME)1,2. However, neuronal cell bodies reside in various PNS ganglia, far from the tumor mass. Thus, cancer or healthy organ-innervating neurons elude current tissue sequencing datasets. To molecularly characterize pancreas- and PDAC-innervating neurons at single cell resolution, we developed 'Trace-n-seq'. This method employs retrograde tracing of axons from tissues to their respective ganglia followed by single-cell isolation and transcriptomic analysis. By characterizing >5.000 individual sympathetic and sensory neurons with about 4.000 innervating PDAC or healthy pancreas we reveal novel neuronal cell types and unique molecular networks distinct to pancreas, pancreatitis, PDAC, or melanoma metastasis. We integrate single-cell datasets of innervating neurons and the TME to establish a neuro-cancer-microenvironment interactome, delineate cancer-driven neuronal reprogramming and generate a pancreatic cancer-nerve signature. Pharmacological denervation induces a proinflammatory TME and increases immune-checkpoint inhibitor effectiveness. Nab-Paclitaxel causes intra-tumor neuropathy which attenuated PDAC growth and in combination with sympathetic denervation results in synergistic tumor regression. Our multi-dimensional data reveal new insights into the networks and functions of PDAC-innervating neurons, supporting inclusion of denervation in future therapies.
LB  - PUB:(DE-HGF)16
C6  - pmid:39961335
DO  - DOI:10.1038/s41586-025-08735-3
UR  - https://inrepo02.dkfz.de/record/298953
ER  -