A glucose-enriched lung pre-metastatic niche triggered by matrix stiffness-tuned exosomal miRNAs in hepatocellular carcinoma

Yingying Zhao, Hongmei Yu, Jiajun Li, Jiali Qian, Miao Li, Xi Zhang, Mimi Wang, Yaohui Wang, Yinying Dong, Yang You, Qiwen Zhou, Dongmei Gao, Yan Zhao, Binbin Liu, Rongxin Chen, Zhenggang Ren, Zhiming Wang (), Kezhi Zhang () and Jiefeng Cui ()
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Yingying Zhao: Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
Hongmei Yu: Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
Jiajun Li: Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
Jiali Qian: Fudan University
Miao Li: Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
Xi Zhang: Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
Mimi Wang: Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
Yaohui Wang: Fudan University Shanghai Cancer Center
Yinying Dong: The Affiliated Hospital of Qingdao University
Yang You: Fudan University
Qiwen Zhou: Fudan University
Dongmei Gao: Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
Yan Zhao: Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
Binbin Liu: Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
Rongxin Chen: Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
Zhenggang Ren: Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
Zhiming Wang: Fudan University
Kezhi Zhang: Nanjing Medical University
Jiefeng Cui: Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education

Nature Communications, 2025, vol. 16, issue 1, 1-26

Abstract: Abstract Apart from the classic features, it is almost unknown whether there exist other new pathological features during pre-metastatic niche formation in hepatocellular carcinoma (HCC). Our previous works have highlighted the contribution of increased matrix stiffness to lung pre-metastatic niche formation and metastasis in HCC. However, whether increased matrix stiffness influences glucose metabolism and supply of lung pre-metastatic niche remains largely unclear. Here we uncover the underlying mechanism by which matrix stiffness-tuned exosomal miRNAs as the major contributor modulate glucose enrichment during lung pre-metastatic niche formation through decreasing the glucose uptake and consumption of lung fibroblasts and increasing angiogenesis and vascular permeability. Our findings suggest that glucose enrichment, a new characteristic of the lung pre-metastatic niche triggered by matrix stiffness-tuned exosomal miRNAs, is essential for the colonization and survival of metastatic tumor cells, as well as subsequent metastatic foci growth.

Date: 2025
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DOI: 10.1038/s41467-025-56878-8

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