Micro-Organ Chip Deciphers Tumor-Derived G-CSF as Remote Commander of Lung Pre-Metastatic Niche via VEGFA-KDR Cascade

  • Adv Sci (Weinh). 2025 Nov 22:e18584. doi: 10.1002/advs.202518584.
Jingxin Zhang  1  2 ,  Xiaoying Huang  1 ,  Lingchuan Ma  1 ,  Zixing Chen  1 ,  Tianyao Li  2  3 ,  Lijian Wang  1 ,  Yutong Guo  1 ,  Hu Xu  2  4 ,  Junqi Li  5  6 ,  Jiang-Jiang Qin  7 ,  Xiang Wang  8 ,  Yuhong Cao  2 ,  Kai Miao  1  9  10
Affiliations
  • 1. Faculty of Health Sciences, University of Macau, Macau SAR, 519000, China.
  • 2. CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing, 100190, China.
  • 3. University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4. College of Ecology, Lanzhou University, Lanzhou, 730000, China.
  • 5. Clinical Research and Translational Medicine Department, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450000, China.
  • 6. Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan, 450000, China.
  • 7. Center for Innovative Drug Research, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310018, China.
  • 8. Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100032, China.
  • 9. MOE Frontier Science Centre for Precision Oncology, University of Macau, Macau SAR, 519000, China.
  • 10. Zhuhai UM Science & Technology Research Institute, Hengqin, 519031, China.
PMID: 41275332 DOI: 10.1002/advs.202518584
Abstract

Metastasis is the leading cause of cancer-related mortality. During metastatic progression, distant organs form a pre-metastatic niche (PMN), creating a permissive microenvironment that facilitates circulating tumor cell (CTC) colonization. To investigate pulmonary PMN formation in breast Cancer, a micro-organ chip is employed that enables contact-independent coculture of tumor and lung tissues. This model reveals that PMN formation is governed by tumor-secreted factors without requiring direct tumor cell contact and exhibits non-tumor-type specificity. It is found that coculture with tumor tissue upregulates vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2/KDR) in lung capillary cells. Through integrated single-cell RNA Sequencing and cytokine array analysis, granulocyte colony stimulating factor (G-CSF) is identified as a key tumor-derived mediator that modulates the pre-metastatic niche through activating the VEGFA-KDR signaling axis in the lung, thereby promoting angiogenesis and PMN development. This study highlights the G-CSF-KDR axis as a potential therapeutic target for inhibiting breast Cancer metastasis.

Keywords
G‐CSF; KDR; angiogenesis; micro‐organ chip; pre‐metastatic niche.
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