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<p>Gastric cancer primarily originates from gastric stem/progenitor cells and is driven by somatic mutations. Although <i>Helicobacter pylori</i> is the main risk factor, how it drives malignancy is still not well understood. Analysis of single-cell RNA sequencing data reveals that human gastric cancer correlates with suppressed BMP signalling, a crucial niche signal for gastric stem cells, in stromal cells rather than epithelial cells. Genetic disruption of BMP signalling in <i>Col1a2</i><sup><i>+</i></sup> stromal cells or <i>Acta2</i><sup><i>+</i></sup> myocytes/pericytes alone, but not in gastric stem cells themselves, triggers mutations in gastric stem cells and initiates cancer development. Mechanistically, loss of BMP signalling increases stromal production of Wnt ligands, which dose-dependently drive transcription-replication collisions, R-loops, and DNA damage in gastric stem cells. The resulting DNA damage and carcinogenesis can be prevented by small-molecule inhibitors targeting Wnt pathway. Importantly, we identify inflammation as a key disruptor of stromal BMP signalling, as seen in patient samples with chronic atrophic gastritis and <i>H. pylori</i>-infected mouse gastric samples, which is associated with DNA damage. Together, these findings show how chronic inflammation derails niche signalling to drive stem cell mutations and gastric cancer and highlight promising avenues for early prevention.</p>

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Stromal BMP signalling maintains stem cell genome integrity and prevents gastric cancer initiation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月17日

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  • Zihao Li,
  • Zhengting Wang,
  • Ruichen Yang,
  • Jiarui Zhao,
  • Shaoyang Zhang,
  • Liuchun Feng,
  • Haiyu Shen,
  • Hua Yue,
  • Zhenlin Zhang,
  • Xiaolin Guo,
  • Dengli Hong,
  • Yuji Mishina,
  • Ye-Guang Chen,
  • Qiang Wu,
  • Huijuan Liu,
  • Baojie Li

摘要

Gastric cancer primarily originates from gastric stem/progenitor cells and is driven by somatic mutations. Although Helicobacter pylori is the main risk factor, how it drives malignancy is still not well understood. Analysis of single-cell RNA sequencing data reveals that human gastric cancer correlates with suppressed BMP signalling, a crucial niche signal for gastric stem cells, in stromal cells rather than epithelial cells. Genetic disruption of BMP signalling in Col1a2+ stromal cells or Acta2+ myocytes/pericytes alone, but not in gastric stem cells themselves, triggers mutations in gastric stem cells and initiates cancer development. Mechanistically, loss of BMP signalling increases stromal production of Wnt ligands, which dose-dependently drive transcription-replication collisions, R-loops, and DNA damage in gastric stem cells. The resulting DNA damage and carcinogenesis can be prevented by small-molecule inhibitors targeting Wnt pathway. Importantly, we identify inflammation as a key disruptor of stromal BMP signalling, as seen in patient samples with chronic atrophic gastritis and H. pylori-infected mouse gastric samples, which is associated with DNA damage. Together, these findings show how chronic inflammation derails niche signalling to drive stem cell mutations and gastric cancer and highlight promising avenues for early prevention.