Researchers at Kanazawa University Cancer Institute and Nano Life Science Institute (WPI-NanoLSI) have uncovered an important mechanism by which stomach cancer metastasizes to distant organs. Their work shows that cancer cells stimulate Wnt signaling in surrounding stromal fibroblasts to produce hyaluronic acid, creating a supportive microenvironment that promotes metastasis.
These findings provide new insights into how metastatic tumors become established and suggest promising strategies to prevent gastric cancer progression.
Big challenges in gastric cancer
Gastric cancer remains one of the leading causes of cancer-related deaths worldwide, primarily because it often metastasizes to other organs, such as the liver. Although the genetic mutations that cause tumors have been extensively studied, the biological mechanisms that allow cancer cells to colonize new tissues are still poorly understood.
Wnt signaling, an essential pathway for stem cell maintenance and tissue regeneration, is often activated by external ligand stimulation rather than genetic mutations in gastric cancer. This study further identified that Wnt signaling in the tumor microenvironment also plays an important role in disease progression.
Cancer cells remodel their surroundings, allowing them to spread
Team leader Masanobu Oshima and his colleagues used advanced mouse and organoid models to study how stomach cancer metastasizes to the liver.
They discovered the following:
• Expression of Wnt ligands promotes liver metastasis of gastric cancer.
• Wnt ligands secreted by tumor cells activate surrounding stromal fibroblasts.
• Wnt signaling cooperates with TGF-β signaling to activate these fibroblasts.
• Activated fibroblasts express Has2 and produce hyaluronic acid, which accumulates at metastatic sites.
• Deposition of hyaluronic acid creates a supportive niche within the liver that allows cancer cells to survive and proliferate.
• Degradation of hyaluronic acid dramatically inhibited metastatic tumor formation.
Importantly, we demonstrated that activation of Wnt signaling within cancer cells alone is not sufficient to cause metastasis, and that stromal Wnt activation is essential.
Hyaluronic acid builds a niche that supports metastasis
Researchers observed significant accumulation of hyaluronic acid in the tumor microenvironment during the early stages of metastasis.
Degrading hyaluronan using hyaluronidase expression significantly reduced liver metastases, demonstrating that stromal hyaluronan plays an important role in metastatic tumor development.
Implications for future treatments
This study highlights the importance of ligand-dependent Wnt signaling in tumor-stromal interactions in cancer progression.
The results suggest promising therapeutic strategies, including:
• Targeting ligand-dependent Wnt signaling.
• Inhibition of hyaluronic acid production
• Disruption of metastatic niche formation
These approaches may help prevent or limit gastric cancer metastasis.
Towards better prevention of metastatic disease
By revealing how cancer cells create a microenvironment that supports metastasis, this study provides a new framework for understanding gastric cancer progression and developing treatments 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 research shows that metastasis is not only caused by cancer cells themselves, but also by how cancer cells remodel surrounding tissues. By creating a supportive environment in distant organs, tumors can survive and grow. Our findings suggest that disrupting the environment that promotes metastasis, rather than targeting cancer cells alone, could represent a powerful new treatment. ”
Masanobu Oshima Kanazawa University WPI Nano Life Science Institute (NanoLSI)
sauce:
Kanazawa University Nano Life Science Institute (NanoLSI)
Reference magazines:
Yuya Furuya others. (2026). Ligand-dependent Wnt signaling promotes gastric cancer metastasis via hyaluronic acid expression in the microenvironment. nature communications. DOI: 10.1038/s41467-026-69470-5. https://www.nature.com/articles/s41467-026-69470-5
