Fan, Weiguo and Adebowale, Kolade and Váncza, Lóránd and Li, Yuan and Rabbi, Md Foysal and Kunimoto, Koshi and Chen, Dongning and Mozes, Gergely and Chiu, David Kung-Chun and Li, Yisi and Tao, Junyan and Wei, Yi and Adeniji, Nia and Brunsing, Ryan L. and Dhanasekaran, Renumathy and Singhi, Aatur and Geller, David and Lo, Su Hao and Hodgson, Louis and Engleman, Edgar G. and Charville, Gregory W. and Charu, Vivek and Monga, Satdarshan P. and Kim, Taeyoon and Wells, Rebecca G. and Chaudhuri, Ovijit and Török, Natalie J. (2024) Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver. Nature. ISSN 0028-0836
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Abstract
Type diabetes mellitus 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. Type diabetes mellitus 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 signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-β1–tensin-1–YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.
Item Type: | Article |
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Subjects: | Euro Archives > Multidisciplinary |
Depositing User: | Managing Editor |
Date Deposited: | 06 Feb 2024 12:40 |
Last Modified: | 06 Feb 2024 12:40 |
URI: | http://publish7promo.com/id/eprint/4428 |