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Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related death.80% of HCC occurs in patients with cirrhosis.The intriguing tumor-stroma and tumor-extracellular matrix interactions,as well as the intricate interplay between biochemical and mechanical cues make HCC microenvironment an extremely interesting but complicated system to study.Cells sense their matrix physical environment through mechanotransduction which translates mechanical cues into biochemical signals,directing subsequent cellular responses to influence cell migration,proliferation and extracellular matrix properties.Disorders in mechanotransduction take part in the development of various diseases such as cancer and cancer metastases.Here we focus on the biomechanics of HCC microenvironment.Using atomic force microscopy (AFM) and ultrasound elastography,we found stiffness heterogeneity in HCC tissues,with alterations corresponding to relative tissue-tumor locations.We confirmed these observations in HCC patients as well as in our syngenic HCC model in which immunocompetent mice induced to have liver cirrhosis were orthotopically seeded with syngenic HCC cells.We further identified changes of actin cytoskeleton and cell-cell adhesions in these phenomena.To study the effects of physiological and pathological ranges of matrix stiffness on HCC development and metastasis,we introduced an in vitro cell culture system using polyacrylamide gel with tunable rigidity.We found that matrix stiffness had profound effects on HCC cells,changing their actin organization,cell migration,proliferation and YAP signaling.These results suggest unique biomechanical features in HCC microenvironment.Studying the underlying mechanisms may contribute to the understanding of hepatocarcinogenesis and the development and metastasis of hepatocarcinoma.