Wnt signaling in fibroblasts drives gastric cancer metastasis to the liver

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 signaling in surrounding stromal fibroblasts to produce hyaluronan, creating a supportive microenvironment that promotes metastasis.

These findings provide new insight into how metastatic tumors establish themselves and suggest promising strategies to prevent gastric cancer progression.

A major challenge in gastric cancer

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 tumors have been extensively studied, the biological mechanisms that allow cancer cells to colonize new tissues remain poorly understood.

"Wnt signaling" - 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 signaling in the tumor microenvironment also plays a crucial role in disease progression.

Cancer cells reshape their surroundings to enable spread

Using advanced mouse and organoid models, team leader Masanobu Oshima and colleagues investigated how gastric cancer spreads to the liver.

They discovered that:
• Wnt ligand expression promotes gastric cancer liver metastasis.
• Tumor cell-secreted Wnt ligands activate surrounding stromal fibroblasts. 
• Wnt signaling cooperates with TGF-β signaling to activate these fibroblasts. 
• Activated 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. 
• Degrading hyaluronan dramatically suppressed metastatic tumor formation.

Importantly, activating Wnt signaling within cancer cells alone was not sufficient to drive metastasis, demonstrating that stromal Wnt activation is essential.

Hyaluronan builds a supportive metastatic niche

The researchers observed substantial hyaluronan accumulation in the tumor 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 tumor development.

Implications for future therapies

This study highlights the importance of ligand-dependent Wnt signaling in tumor–stroma interactions in cancer progression.

The results suggest promising therapeutic strategies, including:
• targeting ligand-dependent Wnt signaling 
• inhibiting hyaluronan production 
• disrupting metastatic niche formation 

These approaches may help prevent or limit gastric cancer metastasis.

Toward better prevention of metastatic disease

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 tumors and exploring therapeutic interventions targeting the tumor microenvironment.

Our study shows that metastasis is driven not only by cancer cells themselves, but by how they reshape the surrounding tissue. By creating a supportive environment in distant organs, tumors 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."

Masanobu Oshima, WPI Nano Life Science Institute (NanoLSI), Kanazawa University