What is it about?
Normally, RNA interference (RNAi) drugs mainly reach liver cells, which limits their use in cancer because most treatments need to target the tumor cells directly. We discovered that a molecule called neuropeptide Y (NPY), produced by liver cells, actually helps cancer cells settle and grow in the liver. NPY acts as a “signal” that attracts metastatic cancer cells to the liver and activates the surrounding tissue. This activation triggers release of TGFβ and further increases NPY production around the metastases, creating a vicious cycle that supports tumor growth. The cancer cells themselves react to this environment by increasing a receptor called Y5R, which recognizes NPY. When NPY binds to Y5R, it helps cancer cells move toward the liver, survive, and multiply by switching on specific signaling pathways inside the cells. To break this harmful cycle, we used lipid nanoparticles to deliver small interfering RNAs (siRNAs) that specifically reduce NPY in liver cells. In preclinical models, this approach successfully reduced liver metastases.
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Photo by National Cancer Institute on Unsplash
Why is it important?
Many cancer-related deaths are not caused by the original tumor, but by its spread (metastasis) to other organs. The liver is one of the most frequently affected organs by such secondary tumors, making it a particularly important target for new treatments. In this setting, communication between (disseminated) tumor cells and organ niches has become a focus in cancer research in recent years. Approved RNA interference (RNAi) therapeutics marked groundbreaking advances. Yet, the clinical translation of RNAi for cancer treatment remains unrealized—largely due to the predominant delivery of siRNAs to hepatocytes. Our study uncovers a novel crosstalk mechanism that shapes the metastatic liver niche, offering a compelling opportunity to transform this apparent limitation into a therapeutic advantage. By selectively targeting NPY expression in hepatocytes, rather than in tumor cells, we introduce a paradigm for the treatment of hepatic metastases.
Perspectives
In this study we found a new way to treat tumors that spread to the liver by turning an existing “problem” of RNA therapies into an advantage. Using RNAi, we were able to interfere with the NPY-Y5R system - a communication system between cancer cells and liver niche -, thereby inhibiting liver metastasis . Through collaboration with outstanding researchers and clinicians, we were able to test our hypothesis in a variety of ways and utilise an arsenal of techniques that make our findings extremely robust. We are very much looking forward to continuing this promising work together.
Laura Wormser
Friedrich-Alexander-Universitat Erlangen-Nurnberg
Read the Original
This page is a summary of: The liver talks back: NPY orchestrates attraction of cancer cells and CHK2-dependent clonogenicity in the metastatic niche, Proceedings of the National Academy of Sciences, November 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2518418122.
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