Extracellular Matrix Viscoelasticity Drives Liver Cancer Progression in Pre-Cirrhotic NASH

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.

Spatial and Temporal Control of 3D Hydrogel Viscoelasticity through Phototuning

“…Several strategies have been employed toward this end, including the use of ionic cross-links, guest–host and other supramolecular interactions, dynamic covalent bonds, and hydrophobic interactions. ,,, These hydrogel systems have been used to interrogate the cellular response to viscoelasticity, a burgeoning area in mechanobiology and 3D culture models. Mesenchymal stem cell spreading, focal adhesion formation, and osteogenic differentiation are significantly enhanced in fast-relaxing matrices. − Viscoelastic matrices have been used to generate, expand, and passage stem cell-derived organoids, and the extent of local viscoelasticity can enable morphogenetic processes such as intestinal organoid budding. ,− The tumor microenvironment is also viscoelastic, and cancer cells are responsive to different rates of stress relaxation through different rates of proliferation, migration, and modes of invasion. − …”

“… 16 , 19 − 21 The tumor microenvironment is also viscoelastic, and cancer cells are responsive to different rates of stress relaxation through different rates of proliferation, migration, and modes of invasion. 22 − 25 …”