Characterization of neuropeptide-receptor cross-talk driving metastatic liver colonization by disseminated cancer cells.

• Applicants: Professorin Dr. Anja-Katrin Bosserhoff; Privatdozent Dr. Peter Dietrich
• Subject Area: Gastroenterology ; Hematology, Oncology ; Cell Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 573697683

Our preliminary data outlines a novel crosstalk between hepatocytes (expressing the ligand neuropeptide Y (NPY)) and cancer cells (expressing the NPY-receptor Y5R) in the metastatic liver niche and highlight RNA interference targeting NPY as a promising therapeutic approach to control liver metastasis. These findings were recently submitted for publication (Wormser L, Fritz V, …, Bosserhoff AK & Dietrich P.) and were now sent out for peer-review. The aim of this study is to further characterize tumor cell plasticity of disseminated cancer cells as well as effects of immune tolerance mediated by a cross-talk between metastatic cells and liver-derived factors which might indicate novel therapeutic opportunities. Following up on our observations in the 1st funding period, we hypothesize that (i) the NPY-system represents a general promotor of liver colonization affecting further types of cancer, (ii) other ligands and receptors of the NPY-family (next to NPY and the Y5-receptor) might be involved in liver metastasis, (iii) resistance mechanisms can emerge when targeting the NPY-Y5R-axis, (iv) the NPY-system modulates immune escape in cancer which could drive liver metastasis. According to hypotheses, we aim to explore the following aspects in more detail: Aim 1: Exploring the NPY-system as a general driver of metastatic liver colonization. A. We aim at expanding our findings in melanoma cells applying several further types of liver metastatic cancer with a special focus on colorectal, pancreatic and breast cancer. B. We aim to explore the role of further NPY-receptors (Y1R, Y2R, Y4R) as well as further members of the NPY-family of peptides (pancreatic polypeptide (PP) and peptide YY (PYY)) in chemotactic liver infiltration/colonization and potential resistance mechanisms via these further receptors and ligands upon therapeutic inhibition of the NPY-Y5R-axis. Aim 2: The potential role of the NPY-system as a mediator of immune-escape in liver metastasis. Several lines of evidence suggested an immunosuppressive role of the NPY system. Therefore, the NPY system could modulate immune escape in cancer which is completely unknown. Hence, one further aim is to analyze the unknown role of the NPY-system as a potential major determinant of immune-surveillance in liver metastasis.

• DFG Programme: Research Grants