Agenda

The peripheral nervous system has emerged as a key regulator of cancer progression. In pancreatic ductal adenocarcinoma (PDAC), the sympathetic branch of the autonomic nervous system has been reported to inhibit cancer development. This inhibition is associated with extensive sympathetic nerve sprouting in early pancreatic cancer precursor lesions. Yet, the mechanisms behind this process remain unknown. In this study, we investigated the role of pancreatic Schwann cells in the structural plasticity of sympathetic neurons. We examined changes in the number and distribution of Schwann cells in a transgenic mouse model of PDAC and in a model of metaplastic pancreatic lesions induced by chronic inflammation. Our results showed that Schwann cells proliferate and expand to cover the new sympathetic nerve sprouts in metaplastic/neoplastic pancreatic lesions. Individual genetic labelling showed that Schwann cells in these lesions have a more elongated and branched structure compared to control tissues. In addition, Schwann cells overexpress pro-inflammatory signals and neurotrophic factors, including GDNF. Sympathetic neurons upregulate GDNF receptor expression and show a growth-promoting response to GDNF in vitro. Finally, selective genetic deletion of Gdnf from Schwann cells completely blocked sympathetic nerve sprouting in pancreatic metaplastic lesions in vivo. Altogether, our data demonstrates that pancreatic Schwann cells undergo adaptive reprogramming during early cancer development and supports a protective anti-tumor neuronal response.