Sympathetic Neurons Restrain Pancreatic Cancer Lung Metastatic seeding through NPY-NPY1R Signaling [barcode]

Here, we investigate the function of sympathetic innervation on pancreatic ductal adenocarcinoma (PDAC) metastasis. Although sympathetic signaling has been shown to promote primary PDAC growth, its contribution to metastatic progression remains poorly defined.

Using a pool of barcoded Kras;Trp53-driven mouse PDAC cell lines that allows quantitative analysis of metastatic seeding and growth, we found that sympathetic innervation restrains metastatic seeding but promotes metastatic outgrowth. In vivo pharmacologic screening showed that inhibition of the Neuropeptide Y (NPY) receptor NPY1R phenocopied the effect of sympathetic ablation on metastatic seeding, indicating sympathetic release of NPY restrains metastatic seeding through NPY1R signaling, likely in lung stromal cells including alveolar fibroblasts.