细胞外基质
粘弹性
癌症研究
机械转化
整合素
癌症
细胞生物学
医学
化学
内科学
生物
受体
材料科学
复合材料
作者
Natalie J. Török,Weiguo Fan,Kolade Adebowale,Yuan Li,Md Foysal Rabbi,Lóránd Váncza,Dongning Chen,Koshi Kunimoto,Gergely Mozes,Yisi Li,Junyan Tao,Satdarshan P. Monga,Gregory W. Charville,Rebecca G. Wells,Renumathy Dhanasekaran,Taeyoon Kim,Ovijit Chaudhuri
出处
期刊:Research Square - Research Square
日期:2022-10-10
被引量:2
标识
DOI:10.21203/rs.3.rs-2087090/v1
摘要
Abstract Type 2 diabetes mellitus (T2DM) is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development, and increased stiffness is known to promote HCC progression in cirrhotic conditions. T2DM is characterized by an accumulation of advanced glycation end products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here, we find that in patients and animal models AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic β-catenin signaling promote HCC induction, while inhibiting AGEs production, reconstituting the clearance receptor AGER1, or breaking AGE-mediated collagen crosslinks reduce viscoelasticity and HCC growth. Matrix analysis and computational modeling demonstrate that lower interconnectivity of AGEs-bundled collagen matrix, marked by shorter fiber length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through integrin β1–Tensin 1–YAP mechanotransduction pathway. These results reveal for the first time that AGEs-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can drive cancer progression in vivo, independent of stiffness.
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