Wnt signaling drives stomach cancer spread by reshaping surrounding tissue

KANAZAWA, Japan, Feb. 25, 2026 /PRNewswire/ — 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 (Fig. 1).
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 (Fig. 2).

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,” says Oshima. “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.”

Figures

Fig 1: https://nanolsi.kanazawa-u.ac.jp/wp/wp-content/uploads/Figure1_Nat-Commun_Feb.2026.jpg

Caption: Wnt ligand expression promotes liver metastasis of gastric cancer.

Two gastric organoid lines, KTP and WKTP were established from mouse stomach epithelium. KTP organoids carry driver mutations in Kras, Tgfbr2, and Trp53, whereas WKTP organoids additionally express Wnt ligand. After spleen transplantation, WKTP organoids–unlike KTP organoids–form multiple liver metastasis (Reproduced from: Yuichiro Furutani et al., Nature Communications (2026), under a CC BY-NC-ND 4.0 License).

Fig.2: https://nanolsi.kanazawa-u.ac.jp/wp/wp-content/uploads/Figure2_eyechatch_Nat-Commun_Feb.2026.jpg

Caption: Ligand-dependent Wnt signaling drives liver metastasis in gastric cancer. Wnt ligand-expressing gastric cancer cells activate Wnt signaling in both tumor cells and surrounding stromal fibroblasts. In the liver metastatic niche, Wnt signaling cooperates with TGF-β signaling to activate cancer-associated fibroblasts (CAFs), inducing hyaluronan production. This hyaluronan-rich stroma supports the establishment and growth of metastatic tumors (Reproduced from: Yuichiro Furutani et al., Nature Communications (2026), under a CC BY-NC-ND 4.0 License).

Reference

Ligand-dependent Wnt signaling promotes gastric cancer metastasis through hyaluronan expression in microenvironment.

Yuichiro Furutani, Hiroko Oshima, Chang Pyo Hong, SeonJu Choi, Ryosuke Machi, Mizuho Nakayama, Kazuhiro Murakami, Shintaro Yagi, Yukinobu Ito, Daichi Maeda, Noriyuki Inaki, Nick Barker and Masanobu Oshima

Nature Communications , Published on line 14 February 2026.

DOI: 10.1038/s41467-026-69470-5

URL: https://www.nature.com/articles/s41467-026-69470-5

Acknowledgements

The authors thank Manami Watanabe and Ayako Tsuda for their technical assistance. This work was supported by Grants-in-Aid for Scientific Research (A) (22H00454 to M.O.), (B) (23K02899 to H.O.), and World Premier International Research Center Initiative (WPI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, and by the Japan Agency for Medical Research and Development (AMED) (24ama22152h0002 to H.O.).

Contact

Kimie Nishimura (Ms)
Project Planning and Outreach, NanoLSI Administration Office
Nano Life Science Institute, Kanazawa University
Email: [email protected]
Kakuma-machi, Kanazawa 920-1192, Japan

Nano Life Science Institute (WPI-NanoLSI), Kanazawa University

Understanding nanoscale mechanisms of life phenomena by exploring ‘uncharted nano-realms.’ Cells are the basic units of life. At NanoLSI, researchers develop nanoprobe technologies that enable direct imaging, analysis, and manipulation of biomolecules such as proteins and nucleic acids inside living cells. By visualizing these processes at the nanoscale, the institute seeks to uncover fundamental principles of life and disease.

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About Kanazawa University

Founded in 1862 in Ishikawa Prefecture, Kanazawa University is one of Japan’s leading comprehensive national universities with a history spanning more than 160 years. With campuses at Kakuma and Takaramachi–Tsuruma, the university upholds its guiding principle of being “a research university dedicated to education, while opening its doors to both local and global society.”

Internationally recognized for its research institutes, including the Nano Life Science Institute (WPI-NanoLSI) and the Cancer Research Institute, Kanazawa University promotes interdisciplinary research and global collaboration, driving progress in health, sustainability, and culture.

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