Pancreatic Schwann cell reprogramming supports cancer-associated neuronal remodeling

Abstract

The peripheral nervous system is a key regulator of cancer progression. In pancreatic ductal adenocarcinoma (PDAC), the sympathetic branch of the autonomic nervous system inhibits cancer development. This inhibition is associated with extensive sympathetic nerve sprouting in early pancreatic cancer precursor lesions. However, the underlying mechanisms behind this process remain unclear. This study aimed to investigate the roles of pancreatic Schwann cells in the structural plasticity of sympathetic neurons. We examined the 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. Schwann cells proliferated and expanded simultaneously with new sympathetic nerve sprouts in metaplastic/neoplastic pancreatic lesions. Sparse genetic labeling showed that individual Schwann cells in these lesions had a more elongated and branched structure than those under physiological conditions. Schwann cells overexpressed proinflammatory and neurotrophic factors, including glial cell-derived neurotrophic factor (GDNF). Sympathetic neurons upregulated the GDNF receptor and promoted cell growth in response to GDNF in vitro. Selective genetic deletion of Gdnf in Schwann cells completely blocked sympathetic nerve sprouting in metaplastic pancreatic lesions in vivo. This study demonstrated that pancreatic Schwann cells underwent adaptive reprogramming during early cancer development, supporting a protective antitumor neuronal response. These finding could help to develop new strategies to modulate cancer associated neural plasticity. MAIN POINTSO_LINon-myelinating pancreatic Schwann cells associate with sympathetic axon terminals supplying the pancreas. C_LIO_LIPancreatic Schwann cells proliferate and undergo adaptive reprogramming in response to chronic inflammation and the development of pancreatic cancer. C_LIO_LIGlial cell line-derived neurotrophic factor expression in reprogrammed pancreatic Schwann cells promotes Schwann cell expansion and sympathetic axon sprouting in pancreatic cancer precursor lesions. C_LI