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

TY - JOUR

T1 - Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer

AU - Guillot, Jérémy

AU - Dominici, Chloé

AU - Lucchesi, Adrien

AU - Nguyen, Huyen Thi Trang

AU - Puget, Angélique

AU - Hocine, Mélanie

AU - Rangel-Sosa, Martha M

AU - Simic, Milesa

AU - Nigri, Jérémy

AU - Guillaumond, Fabienne

AU - Bigonnet, Martin

AU - Dusetti, Nelson

AU - Perrot, Jimmy

AU - Lopez, Jonathan

AU - Etzerodt, Anders

AU - Lawrence, Toby

AU - Pudlo, Pierre

AU - Hubert, Florence

AU - Scoazec, Jean-Yves

AU - van de Pavert, Serge A

AU - Tomasini, Richard

AU - Chauvet, Sophie

AU - Mann, Fanny

N1 - © 2022. The Author(s).

PY - 2022/4

Y1 - 2022/4

N2 - 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.

AB - 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.

KW - Animals

KW - Carcinoma, Pancreatic Ductal

KW - Macrophages

KW - Mice

KW - Pancreatic Neoplasms

KW - Sympathetic Nervous System/physiology

KW - Tumor Microenvironment

KW - DUCTAL ADENOCARCINOMA

KW - INITIATION

KW - INNERVATION

KW - COOPERATE

KW - PAIN

KW - REDUCES SURVIVAL

KW - NEURONS

KW - SENSATION

KW - TUMOR-GROWTH

KW - PROGRESSION

U2 - 10.1038/s41467-022-29659-w

DO - 10.1038/s41467-022-29659-w

M3 - Journal article

C2 - 35418199

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1985

ER -