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, You Yang, Qiwen Zhou, Dongmei Gao, Yan Zhao, Binbin Liu, Rongxin Chen, Zhenggang Ren, Zhiming Wang, K. Zhang, Jiefeng Cui
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. The mechanisms involved in the formation of the premetastatic niche in hepatocellular carcinoma (HCC) are not completely elucidated. Here, the authors show that matrix stiffness in HCC induces cancer-exosome release which increases glucose availability in the lung premetastatic niche favouring metastasis formation and growing.