Targeting the Npy/Npy1r Signaling Axis in Mutant p53 Driven Pancreatic Cancer Impairs Metastasis

Pancreatic Cancer (PC) is a highly metastatic malignancy. Over 80% of PC patients present with distant disease, preventing potentially curative surgery. The Neuropeptide Y (NPY) system, best known for its role in controlling energy homeostasis, has also been shown to promote tumorigenesis in a range of cancer types, but its role in PC has yet to be explored. Here, we show that expression of NPY and NPY1R are upregulated in mouse PC models and human PC patients. Moreover, using the genetically engineered, autochthonous KPR172HC mouse model of PC we demonstrate that pancreas-specific and whole-body knockout of Npy1r significantly decreases metastasis to the liver. We identify that treatment with the NPY1R antagonist BIBO3304 significantly reduces KPR172HC migratory capacity on cell-derived matrices. Importantly, pharmacological NPY1R inhibition in an intrasplenic model of PC metastasis recapitulated the results of our genetic studies, with BIBO3304 significantly decreasing metastasis in the liver. Together, our results reveal that NPY/NPY1R signaling is a novel anti-metastatic target in PC. Overall design: The genetically engineered KPR172HC mouse model of pancreatic cancer (Hingorani et al. Cancer Cell 2005; Morton et al. PNAS 2009) was crossed with whole-body Npy1r knock-out mice (Zhang et al. International Journal of Obesity 2010; Yan et al. Nature Communications 2021). Primary tumors were isolated at end-stage from KPR172HC Npy1r wildtype mice and KPR172HC Npy1r-/- mice and subjected to RNA-seq (n=10 tumors per genotype).