Zhenxiong Zhao, Si Xiong, Ergang Guo, Hua Huang, Yu Zhang
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引用次数: 0
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.
期刊介绍:
Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior.
Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.