# A Novel Zebrafish Liver‐Specific Metastasis Model Reveals c‐Met as a Driver of Liver Tropism

## TL;DR

Researchers created a new zebrafish model to study liver metastasis and found that high c-Met expression in cancer cells increases their spread to the liver.

## Contribution

The novel zLiverMet model enables visualization of liver metastasis in zebrafish and identifies c-Met as a key driver of liver tropism.

## Key findings

- Cancer cell lines with high c-Met expression showed strong liver tropism in the zLiverMet model.
- Pharmacological inhibition of c-Met reduced liver colonization by cancer cells.
- The zLiverMet model successfully mimics intrahepatic metastasis and offers a scalable platform for drug testing.

## Abstract

Intrahepatic metastasis negatively impacts the prognosis of several cancers, including hepatocellular and colorectal carcinoma. Zebrafish larval xenografts serve as a robust vertebrate platform that allows direct visualisation of tumour behaviour within a living organism. However, organ‐specific metastasis models in zebrafish remain limited, and liver metastasis has not yet been demonstrated. This study aimed to establish a zebrafish larval intrahepatic metastasis model and to determine the role of c‐Met activation in mediating liver tropism of cancer cells.

An intravenous injection–based zebrafish model (zLiverMet) was developed using a liver‐specific fluorescent reporter line to visualise tumour colonisation in vivo. Liver cancer cell lines with distinct c‐Met expression and activation levels were injected into 2‐day post‐fertilisation larvae. The effects of c‐Met overexpression and pharmacological inhibition on intrahepatic metastasis were analysed through confocal imaging and quantitative image measurements. The model's applicability was further tested using colorectal cancer (CRC) cell lines.

Intravenous injection facilitated efficient intrahepatic colonisation, whereas yolk‐sac injection failed to reproduce vascular dissemination. Liver cancer cell lines with high c‐Met expression, SNU‐449, Mahlavu and SK‐HEP‐1, exhibited strong liver tropism, while cell lines with no/low c‐Met expression, HuH‐7 and SNU‐398, showed minimal hepatic metastasis. Overexpressing c‐Met increased liver colonisation of HCC cells, and inhibiting c‐Met activation with the c‐Met inhibitor SU11274 reduced this effect.

The zLiverMet model successfully mimics intrahepatic metastasis and highlights c‐Met as a driver of liver tropism. This zebrafish‐based model offers an ‘organism‐on‐a‐chip’ platform that is rapid, imageable and scalable—bridging in vitro assays and in vivo models for mechanistic and therapeutic studies of liver metastasis.

We developed a new zebrafish model, zLiverMet, to monitor the spread of cancer cells to the liver. We found that cancer cells with high c‐Met expression were more likely to form liver metastases, while blocking c‐Met activation reduced this spread. This model provides a rapid method for studying liver metastasis and testing drugs that may prevent it.