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

The sympathetic nervous system regulates physiological homeostasis, but is increasingly recognized as a context dependent modulator of carcinogenesis. 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. Single-cell transcriptional analyses revealed that NPY1R signaling affects alveolar fibroblasts and intermediate gCap endothelial cells, providing a mechanism for restraining vascular permeability and cancer cell seeding. Together, these findings uncover an unexpected metastasis-protective function of sympathetic innervation, distinct from its effect on metastatic growth, and identify a novel sympathetic-stromal signaling axis that regulates the vascular niche during PDAC lung metastasis.