Hepatocyte-derived NPY promotes liver metastasis

RNA-interference (RNAi) therapeutics represent breakthrough discoveries, but their use in cancer remains limited due to hepatocyte-specific targeting. Cancer metastasis is regulated by complex crosstalk between tumour cells and niche-derived factors. However, the molecular mechanisms enabling metastatic seeding and outgrowth in the liver remain incompletely understood, representing a major clinical challenge. We identified neuropeptide Y (NPY) as a novel promotor of liver metastasis. Hepatocyte-derived NPY attracts metastatic tumor cells to the liver niche. Subsequent microenvironment activation induces TGFbeta, promoting a vicious cycle of peri-metastatic NPY secretion and liver metastasis. Concomitantly, cancer cells upregulate the NPY-5-receptor (Y5R) which is correlated with liver metastasis. NPY-Y5R-crosstalk drives pro-metastatic cell-cell communication and chemotactic migration via cAMP- and ERK-signaling. Moreover, NPY-Y5R-activation dephosphorylates checkpoint kinase 2 (CHK2) to promote clonogenicity and proliferation of cancer cells. Lipid nanoparticles (LNPs) are a promising drug-delivery vehicle for siRNAs. LNPs carrying siRNA-pools targeting NPY were designed and preclinical studies provided evidence for efficacy for the treatment of liver metastasis. Our findings transform the limitation of hepatocyte-specificity of RNA-interference into a therapeutic advantage, introducing a novel paradigm for the treatment of hepatic metastases.