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<p>The majority of gastric cancer cells proliferate in a Wnt ligand-dependent manner. To investigate this, we generated mice harboring <i>Kras</i>, <i>Tgfbr2</i>, and <i>Trp53</i> (KTP) as well as with the same mutations plus <i>Wnt1</i> expression (WKTP) in gastric mucosa. While KTP mice develop gastric metaplasia, WKTP mice develop dysplastic tumors, highlighting the role of ligand-dependent Wnt signaling in primary tumorigenesis. Organoids derived from WKTP mice form liver metastases following splenic transplantation, whereas KTP organoids do not. Notably, <i>Apc</i> disruption fails to induce metastasis of KTP cells, suggesting that stromal Wnt signaling promotes metastasis. Mechanistically, tumor-derived Wnt ligands cooperate with TGFβ signaling to induce <i>Has2</i> expression in cancer-associated fibroblasts (CAFs), leading to hyaluronan accumulation in the metastatic microenvironment. Strikingly, hyaluronidase expression in WKTP cells significantly suppresses liver metastasis. Here we show the critical role of ligand-dependent Wnt signaling and <i>Has2</i>-mediated hyaluronan deposition in metastasis, offering potential therapeutic strategy against gastric cancer metastasis.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月14日

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  • 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,
  • Masanobu Oshima

摘要

The majority of gastric cancer cells proliferate in a Wnt ligand-dependent manner. To investigate this, we generated mice harboring Kras, Tgfbr2, and Trp53 (KTP) as well as with the same mutations plus Wnt1 expression (WKTP) in gastric mucosa. While KTP mice develop gastric metaplasia, WKTP mice develop dysplastic tumors, highlighting the role of ligand-dependent Wnt signaling in primary tumorigenesis. Organoids derived from WKTP mice form liver metastases following splenic transplantation, whereas KTP organoids do not. Notably, Apc disruption fails to induce metastasis of KTP cells, suggesting that stromal Wnt signaling promotes metastasis. Mechanistically, tumor-derived Wnt ligands cooperate with TGFβ signaling to induce Has2 expression in cancer-associated fibroblasts (CAFs), leading to hyaluronan accumulation in the metastatic microenvironment. Strikingly, hyaluronidase expression in WKTP cells significantly suppresses liver metastasis. Here we show the critical role of ligand-dependent Wnt signaling and Has2-mediated hyaluronan deposition in metastasis, offering potential therapeutic strategy against gastric cancer metastasis.