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

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.

Tumorigenesis and axons regulation for the pancreatic cancer: a mathematical approach

“…Data were obtained from the KIC (LSL-KrasG12D/+; Cdkn2a (Ink4a/Arf)lox/lox; Pdx1-Cre) transgenic mouse model of PDAC and describe the percentage of acinar tissue, ADM, PanIN and PDAC in histological sections throuth the pancreas of a 6.5 weeks-old mouse (45 days). Quantification data have been published and are available in the source data file of [2]. Because of the variability between samples, we choose to aggregate all the information contained in each section of the same mouse.…”

“…The axon density was calculated as follows: dendrite length sum (nm) / volume of ROI (µm 3 ). The full protocol and the quantification data for the sympathetic axons are available in the source data file of [2].The quantification data for parasympathetic and sensory fibers are performed using the same protocol. Densities of autonomic axons are the sum of sympathetic and parasympathetic axons in each ROI.…”

“…• in [2] and [11] , it has been observed that the denervation of the autonomic axons has a pro-tumoral effect. The protumoral effect of the denervation is also observed in the numerical simulation in Figure 7.…”

“…In recent decades, the impact of the microenviroment on tumour progression has become widely recognized, which has led to the development of new therapies such as immunotherapies. More recently, it has been shown that fibers of the nervous system infiltrate the tumor microenvironment where they also participate in the regulation of cancer development and progression [2]. It is therefore relevant to study the neurobiology of cancers through mathematical modelling in order to simulate the responses of cancer cells to innervation and predict at long term the effects of therapies targeting neuron-tumor interactions.…”

“…In this article, we developed an ordinary differential equation (ODE) model that describes and simulates the relationship between the PNS and pancreatic cancer development. The model is based on and calibrated with experimental data obtained from a genetically engineered mouse model of PDAC, in which the innervation of early pre-cancerous lesions and cancer have been characterized by three-dimensional (3D) histology (c.f [2]). This model aims to investigate how dynamic changes in the neuronal composition of the microenvironment influence tumor progression.…”