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

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.