112 Researchers at the Cancer Research Institute and the Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, have uncovered a critical mechanism that enables gastric cancer to spread to distant organs. Their study shows that cancer cells stimulate Wnt signalling in surrounding stromal fibroblasts to produce hyaluronan, creating a supportive microenvironment that promotes metastasis. These findings provide new insight into how metastatic tumours establish themselves and suggest promising strategies to prevent gastric cancer progression. The study was recently published in the Nature Communications. Gastric cancer remains one of the leading causes of cancer-related deaths worldwide, largely because it frequently spreads to other organs such as the liver. While genetic mutations that initiate tumours have been extensively studied, the biological mechanisms that allow cancer cells to colonise new tissues remain poorly understood. “Wnt signalling” — a pathway essential for stem cell maintenance and tissue regeneration — is often activated in gastric cancer through external ligand stimulation rather than genetic mutation. This study further identifies that Wnt signalling in the tumour microenvironment also plays a crucial role in disease progression. Using advanced mouse and organoid models, team leader Masanobu Oshima and colleagues investigated how gastric cancer spreads to the liver. The researchers discovered that Wnt ligand expression promotes gastric cancer liver metastasis. Tumour cell-secreted Wnt ligands activate surrounding stromal fibroblasts, and Wnt signalling cooperates with TGF-β signalling to activate these fibroblasts. Once activated, the fibroblasts express Has2, producing hyaluronan that accumulates in metastatic sites. Hyaluronan deposition creates a supportive niche that enables cancer cells to survive and grow in the liver. When hyaluronan was degraded, metastatic tumour formation was dramatically suppressed. Importantly, activating Wnt signalling within cancer cells alone was not sufficient to drive metastasis, demonstrating that stromal Wnt activation is essential. The researchers observed substantial hyaluronan accumulation in the tumour microenvironment during early stages of metastasis. When hyaluronan was degraded using hyaluronidase expression, liver metastasis was markedly reduced, demonstrating that stromal hyaluronan plays a crucial role in metastatic tumour development. This study highlights the importance of ligand-dependent Wnt signalling in tumour–stroma interactions in cancer progression. The results suggest promising therapeutic strategies, including targeting ligand-dependent Wnt signalling, inhibiting hyaluronan production, and disrupting metastatic niche formation. These approaches may help prevent or limit gastric cancer metastasis. By revealing how cancer cells create a supportive metastatic microenvironment, this research provides a new framework for understanding gastric cancer progression and developing therapies aimed at preventing metastatic spread. Future studies will focus on validating these mechanisms in human metastatic tumours and exploring therapeutic interventions targeting the tumour microenvironment. “Our study shows that metastasis is driven not only by cancer cells themselves, but by how they reshape the surrounding tissue,” says Oshima. “By creating a supportive environment in distant organs, tumours are able to survive and grow. Instead of targeting cancer cells alone, our findings suggest that disrupting the environment that supports metastasis could be a powerful new therapeutic approach.”