Autophagic Schwann cells promote perineural invasion mediated by the NGF/ATG7 paracrine pathway in pancreatic cancer

Wunai Zhang,Wenbin Yang,Zeen Zhu,Zheng Wang,Junhui Li,Qinggong Yuan,Jing Zhang,Jixin Wang,Shuo Chen,Yan Zhang,Simei Zhang,Rui He,Weifan Zhang,Yang Liu

doi:10.1186/s13046-021-02198-w

Abstract

BackgroundPerineural invasion (PNI) and autophagy are two common features in the tumor microenvironment of pancreatic cancer (PanCa) and have a negative effect on prognosis. Potential mediator cells and the molecular mechanism underlying their relationships need to be fully elucidated.MethodsTo investigate the autophagy of Schwann cells (SCs) in PNI, we reproduced the microenvironment of PNI by collecting clinical PNI tissue, performing sciatic nerve injection of nude mice with cancer cells and establishing a Dorsal root ganglion (DRG) coculture system with cancer cell lines. Autophagy was detected by IHC, IF, transmission electron microscopy (TEM) and western blotting assays. Apoptosis was detected by IF, TEM and western blotting. NGF targeting molecular RO 08–2750(RO) and the autophagy inhibitor Chloroquine (CQ) were utilized to evaluate the effect on autophagy and apoptosis in SCs and PanCa cells in PNI samples.ResultsSC autophagy is activated in PNI by paracrine NGF from PanCa cells. Autophagy-activated Schwann cells promote PNI through a) enhanced migration and axon guidance toward PanCa cells and b) increased chemoattraction to PanCa cells. The NGF-targeting reagent RO and autophagy inhibitor CQ inhibited Schwann cell autophagic flux and induced Schwann cell apoptosis. Moreover, RO and CQ could induce PanCa cell apoptosis and showed good therapeutic effects in the PNI model.ConclusionsPanCa cells can induce autophagy in SCs through paracrine pathways such as the NGF/ATG7 pathway. Autophagic SCs exert a “nerve-repair like effect”, induce a high level of autophagy of cancer cells, provide a “beacon” for the invasion of cancer cells to nerve fibers, and induce directional growth of cancer cells. Targeting NGF and autophagy for PNI treatment can block nerve infiltration and is expected to provide new directions and an experimental basis for the research and treatment of nerve infiltration in pancreatic cancer.

Highlights

Perineural invasion (PNI) and autophagy are two common features in the tumor microenvironment of pancreatic cancer (PanCa) and have a negative effect on prognosis
Schwann cell autophagy is activated in PNI To confirm the existence of Schwann cells and explore their autophagic status in PNI, we selected 10 PanCa tissues and tissues adjacent to carcinoma for our clinical study
Schwann cells were labeled with GFAP, and neurons were stained with silver staining (Fig. 1A)

Summary

Introduction

Perineural invasion (PNI) and autophagy are two common features in the tumor microenvironment of pancreatic cancer (PanCa) and have a negative effect on prognosis. Perineural invasion (PNI), with a prevalence between 70 and 100% in PanCa, is associated with poor prognosis, tumor recurrence, and generation of pain; this condition can be detected in the early stages and is an independent prognostic factor of PanCa [5, 6]. The Schwann cell-directed regulation of cancer cells may be mediated by neural cell adhesion molecule 1 (NCAM1) in perineural invasion [9]. Schwann cells contribute to PanCa epithelial-mesenchymal transition (EMT) in pancreatic nerves by activating the MET pathway in cancer cells in the PanCa microenvironment [11]. SCs are dedifferentiated and participated in axonal regeneration after peripheral nerve injury, which is critical to achieving efficient axonal regeneration at the early stages [13]

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Conclusion