Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer

Jérémy Guillot, Chloé Dominici, Adrien Lucchesi, Huyen Thi Trang Nguyen, Angélique Puget, Mélanie Hocine, Martha M. Rangel-Sosa, Milesa Simic, Jérémy Nigri, Fabienne Guillaumond, Martin Bigonnet, Nelson Dusetti, Jimmy Perrot, Jonathan Lopez, Anders Etzerodt, Toby Lawrence, Pierre Pudlo, Florence Hubert, Jean-Yves Scoazec, Serge A. Pavert, Richard Tomasini, Sophie Chauvet and Fanny Mann ()
Additional contact information
Jérémy Guillot: Aix Marseille Univ, CNRS, IBDM
Chloé Dominici: Aix Marseille Univ, CNRS, IBDM
Adrien Lucchesi: Aix Marseille Univ, CNRS, IBDM
Huyen Thi Trang Nguyen: Aix Marseille Univ, CNRS, IBDM
Angélique Puget: Aix Marseille Univ, CNRS, IBDM
Mélanie Hocine: Aix Marseille Univ, CNRS, IBDM
Martha M. Rangel-Sosa: Aix Marseille Univ, CNRS, IBDM
Milesa Simic: Aix Marseille Univ, CNRS, INSERM, CIML
Jérémy Nigri: Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM
Fabienne Guillaumond: Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM
Martin Bigonnet: Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM
Nelson Dusetti: Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM
Jimmy Perrot: Lyon Sud University Hospital, Hospices Civils de Lyon
Jonathan Lopez: Lyon Sud University Hospital, Hospices Civils de Lyon
Anders Etzerodt: Aix Marseille Univ, CNRS, INSERM, CIML
Toby Lawrence: Aix Marseille Univ, CNRS, INSERM, CIML
Pierre Pudlo: Aix Marseille Univ, CNRS, Centrale Marseille, I2M
Florence Hubert: Aix Marseille Univ, CNRS, Centrale Marseille, I2M
Jean-Yves Scoazec: Gustave Roussy Cancer Campus
Serge A. Pavert: Aix Marseille Univ, CNRS, INSERM, CIML
Richard Tomasini: Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM
Sophie Chauvet: Aix Marseille Univ, CNRS, IBDM
Fanny Mann: Aix Marseille Univ, CNRS, IBDM

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Neuronal nerve processes in the tumor microenvironment were highlighted recently. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via conventional histological preparations. Here, we employ three-dimensional (3D) imaging of cleared tissues for a comprehensive analysis of sympathetic innervation in a murine model of pancreatic ductal adenocarcinoma (PDAC). Our results support two independent, but coexisting, mechanisms: passive engulfment of pre-existing sympathetic nerves within tumors plus an active, localized sprouting of axon terminals into non-neoplastic lesions and tumor periphery. Ablation of the innervating sympathetic nerves increases tumor growth and spread. This effect is explained by the observation that sympathectomy increases intratumoral CD163+ macrophage numbers, which contribute to the worse outcome. Altogether, our findings provide insights into the mechanisms by which the sympathetic nervous system exerts cancer-protective properties in a mouse model of PDAC.

Date: 2022
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DOI: 10.1038/s41467-022-29659-w

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