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<p>Metastasis remains the primary cause of mortality in pancreatic ductal adenocarcinoma (PDAC). Circulating tumor cells (CTCs) are key players in metastasis, yet the mechanisms governing CTCs formation and survival are incompletely understood. Here, we identify ITGA3 as a key driver of CTCs generation and metastatic progression in PDAC. Integrated proteomic and transcriptomic analyses, coupled with clinical specimen validation, revealed that ITGA3 expression positively correlates with CTCs abundance and poor prognosis. Mechanistically, ITGA3 promotes epithelial–mesenchymal transition (EMT), enhances matrix metalloproteinase expression, and facilitates tumor cell detachment, thereby initiating CTCs formation. Importantly, cancer-associated fibroblasts (CAFs) secrete laminin-332 (LAM332), which engages ITGA3 on PDAC cells to promote proliferation and invasion, drive homotypic CTC clustering, and suppress apoptosis, collectively sustaining CTCs' survival. Neutralization of CAFs-derived LAM332 impaired tumor cell proliferation and invasion, disrupted CTC cluster formation, increased apoptosis, reduced hepatic and pulmonary metastasis, and prolonged survival in mouse models. These findings uncover a CAFs–LAM332–ITGA3 axis that orchestrates CTCs formation and survival, and highlight this stromal–tumor interaction as a promising therapeutic target to mitigate metastatic progression in PDAC.</p>

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CAFs-derived LAM332 promotes CTCs formation and survival via ITGA3 and contributes to the metastasis of pancreatic ductal adenocarcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Haodong Tang,
  • Wenyuan Shi,
  • Siyuan Tan,
  • Zheng Zhang,
  • Qiannan Zhang,
  • Pengcheng Zhou,
  • Yang Wang,
  • Zhengqing Lei,
  • Fangfang Hu,
  • Shan Gao,
  • Jiahua Zhou

摘要

Metastasis remains the primary cause of mortality in pancreatic ductal adenocarcinoma (PDAC). Circulating tumor cells (CTCs) are key players in metastasis, yet the mechanisms governing CTCs formation and survival are incompletely understood. Here, we identify ITGA3 as a key driver of CTCs generation and metastatic progression in PDAC. Integrated proteomic and transcriptomic analyses, coupled with clinical specimen validation, revealed that ITGA3 expression positively correlates with CTCs abundance and poor prognosis. Mechanistically, ITGA3 promotes epithelial–mesenchymal transition (EMT), enhances matrix metalloproteinase expression, and facilitates tumor cell detachment, thereby initiating CTCs formation. Importantly, cancer-associated fibroblasts (CAFs) secrete laminin-332 (LAM332), which engages ITGA3 on PDAC cells to promote proliferation and invasion, drive homotypic CTC clustering, and suppress apoptosis, collectively sustaining CTCs' survival. Neutralization of CAFs-derived LAM332 impaired tumor cell proliferation and invasion, disrupted CTC cluster formation, increased apoptosis, reduced hepatic and pulmonary metastasis, and prolonged survival in mouse models. These findings uncover a CAFs–LAM332–ITGA3 axis that orchestrates CTCs formation and survival, and highlight this stromal–tumor interaction as a promising therapeutic target to mitigate metastatic progression in PDAC.