2. Academic Validation
  3. PDPN+LTBP1+ cancer-associated fibroblasts induce a liver pre-metastatic niche in gastric cancer via PDPN/YAP/LTBP1 and CCL11/CCR3 axis

PDPN+LTBP1+ cancer-associated fibroblasts induce a liver pre-metastatic niche in gastric cancer via PDPN/YAP/LTBP1 and CCL11/CCR3 axis

  • Cell Commun Signal. 2025 Sep 30;23(1):402. doi: 10.1186/s12964-025-02379-6.
Zhenxiong Zhao # 1 2 3,  Si Xiong # 4,  Ergang Guo 5,  Hua Huang 6 7,  Yu Zhang 8 9
Affiliations

Affiliations

  • 1 Department of Gastric Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032, China.
  • 2 Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai, 200032, China.
  • 3 Department of Endoscopy, Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.
  • 4 Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 5 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 6 Department of Gastric Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032, China. huahuang@fudan.edu.cn.
  • 7 Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai, 200032, China. huahuang@fudan.edu.cn.
  • 8 Department of Gastric Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032, China. yu_zhang@fudan.edu.cn.
  • 9 Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai, 200032, China. yu_zhang@fudan.edu.cn.
  • # Contributed equally.
PMID: 41029689 DOI: 10.1186/s12964-025-02379-6
Abstract

As a key component of the tumor microenvironment, cancer-associated fibroblasts (CAFs) exhibit substantial heterogeneity and contribute significantly to tumor growth and progression. However, their involvement in shaping the pre-metastatic niche remains insufficiently characterized. This study demonstrates that extracellular vesicles (EVs) regulated by YAP signaling in podoplanin (PDPN)⁺LTBP1⁺ CAFs activate hepatic stellate cells (HSCs), thereby enhancing gastric Cancer (GC) cell colonization in the liver. Mass spectrometry profiling of EVs from PDPN⁺ and PDPN⁻ CAFs identified latent transforming growth factor beta-binding protein 1 (LTBP1) as a key mediator driving the phenotypic conversion of HSCs into CAF-educated HSCs (CEHs). Exposure to LTBP1-deficient EVs resulted in attenuated CEH-induced malignancy in HGC27 and AGS GC cells. Integrated RNA Sequencing and cytokine array analyses further revealed that LTBP1-containing EVs activated TGF-β signaling in HSCs, leading to CCL11 secretion. This chemokine, in turn, recruited CCR3⁺ metastatic cells to the liver microenvironment. Using a GC liver metastasis model in combination with PET-CT imaging, inhibition of the CCL11/CCR3 axis was shown to suppress CEH-driven tumor growth and metastatic potential. These findings identify LTBP1-enriched EVs from PDPN⁺LTBP1⁺ CAFs as a viable therapeutic target to impede GC liver metastasis.

Keywords

CCL11; Cancer-associated fibroblast; Extracellular vesicle; LTBP1; Podoplanin; TGF-β signaling pathway; YAP.

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