Pancreatic cancer cell-derived semaphorin 3A promotes neuron recruitment to accelerate tumor growth and dissemination

Perineural invasion and neurogenesis are frequently observed in pancreatic ductal adenocarcinoma (PDAC), and they are associated with a poor prognosis. Axon guidance factor semaphorin 3A (SEMA3A) is upregulated in PDAC. However, it remains unclear whether cancer-derived SEMA3A influences nerve innervation and pancreatic tumorigenesis. In silico analyses were performed using PROGgene and NetworkAnalyst to clarify the importance of SEMA3A and its receptors, plexin A1 (PLXNA1) and neuropilin 2 (NRP2), in pancreatic cancer. In vitro assays, including migration, neurite outgrowth, and 3D recruitment, were performed to study the effects of SEMA3A on neuronal behaviors. Additionally, an orthotopic animal study using C57BL/6 mice was performed to validate the in vitro findings. Expression of SEMA3A and its receptors predicted worse prognosis for PDAC. Cancer-derived SEMA3A promoted neural migration, neurite outgrowth, and neural recruitment. Furthermore, SEMA3A-induced effects depended on PLXNA1, NRP2, and MAPK activation. Trametinib, an approved MAPK kinase (MEK) inhibitor, counteracted SEMA3A-enhanced neuronal activity in vitro. Inhibition of SEMA3A by shRNA in pancreatic cancer cells resulted in decreased neural recruitment, tumor growth, and dissemination in vivo. Our results suggested that cancer-secreted SEMA3A plays an important role in promoting neo-neurogenesis and progression of PDAC.