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

  • Nat Commun. 2025 Feb 18;16(1):1736. doi: 10.1038/s41467-025-56878-8.
Yingying Zhao  #  1 ,  Hongmei Yu  #  1 ,  Jiajun Li  #  1 ,  Jiali Qian  2 ,  Miao Li  1 ,  Xi Zhang  1 ,  Mimi Wang  1 ,  Yaohui Wang  3 ,  Yinying Dong  4 ,  Yang You  5 ,  Qiwen Zhou  5 ,  Dongmei Gao  1 ,  Yan Zhao  1 ,  Binbin Liu  1 ,  Rongxin Chen  1 ,  Zhenggang Ren  1 ,  Zhiming Wang  6 ,  Kezhi Zhang  7 ,  Jiefeng Cui  8
Affiliations
  • 1. Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, PR China.
  • 2. Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, PR China.
  • 3. Department of Interventional Radiology, Fudan University Shanghai Cancer Center, Shanghai, PR China.
  • 4. Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao, PR China.
  • 5. Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, PR China.
  • 6. Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, PR China. [email protected].
  • 7. Department of Hepatobiliary Surgery, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu Province, PR China. [email protected].
  • 8. Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, PR China. [email protected].
  • # Contributed equally.
PMID: 39966385 DOI: 10.1038/s41467-025-56878-8
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.

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