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

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.