Journal Article

DKFZ-2025-00387

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Characterization of single neurons reprogrammed by pancreatic cancer.

Thiel, V. (First author)DKFZ* ; Renders, S. (First author)DKFZ* ; Panten, J. (First author)DKFZ* ; Dross, N. ; Bauer, K.DKFZ* ; Azorin, D.DKFZ* ; Henriques, V. ; Vogel, V. ; Klein, C.DKFZ* ; Leppä, A.-M.DKFZ* ; Barriuso Ortega, I.DKFZ* ; Schwickert, J.DKFZ* ; Ourailidis, I. ; Mochayedi, J. ; Mallm, J.-P.DKFZ* ; Müller-Tidow, C. ; Monyer, H.DKFZ* ; Neoptolemos, J. ; Hackert, T. ; Stegle, O.DKFZ* ; Odom, D.DKFZ* ; Offringa, R.DKFZ* ; Stenzinger, A. ; Winkler, F.DKFZ* ; Sprick, M.DKFZ* ; Trumpp, A. (Last author)DKFZ*

2025
Nature Publ. Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41586-025-08735-3

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, 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.

Note: #EA:A010#LA:A010# / 640, pages 1042–1051 (2025)

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Contributing Institute(s):

1. A010 Stammzellen und Krebs (A010)
2. DKTK HD zentral (HD01)
3. A230 Klinische Neurobiologie (A230)
4. B260 Bioinformatik der Genomik und Systemgenetik (B260)
5. B270 Regulatorische Genomik und Evolution von Tumoren (B270)
6. Molekulare Grundlagen Gastrointestinaler Tumoren (D200)
7. KKE Neuroonkologie (B320)
8. Single-cell Open Lab (W192)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2025

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; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 60 ; Index Chemicus ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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