Characterization of single neurons reprogrammed by pancreatic cancer
Vera Thiel, Simon Renders, Jasper Panten, Nicolas Dross, Katharina Bauer, Daniel Azorín, 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 P. Neoptolemos, Thilo Hackert, Oliver Stegle, Duncan T. Odom, Rienk Offringa, Albrecht Stenzinger, Frank Winkler, Martin R. Sprick, Andreas Trumpp
Abstract
. 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.