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Extracellular Matrix Viscoelasticity Promotes 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 b-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, enhance 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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE245016 | GEO | 2023/10/14

REPOSITORIES: GEO

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Project description:Treating recurrent GBM is a clinical challenge due to its highly resistant and aggressive nature. In order to develop new therapeutic targets for recurrent GBM a better understanding of its molecular landscape is necessary. Here we used a cellular model, developed in our lab which generates paired primary and recurrent samples from GBM cell lines and primary patient samples hence allowing us to compare the molecular differences between the two populations. Total RNA seq analysis of parent and recurrent population of two cell lines and one patient sample revealed a significant upregulation of Extracellular matrix interaction in recurrent population. Since matrix stiffness plays a pivotal role in cell-ECM interaction and downstream signaling, we developed a system that mimicked the brain like substrate stiffness by using collagen coated polyacrylamide-based substrate whose stiffness can be modified from normal brain (0.5kPa) to tumorigenic (10kPa). Using these substrates, we were able to capture the morphological and physiological differences between parent and recurrent GBM which were not evident on plastic surfaces (~1 GPa). On 0.5kPa, unlike circular parent cells, recurrent GBM cells showed two morphologies (circular and elongated). The recurrent cells growing on 0.5kPa also showed higher proliferation, invasion, migration and in-vivo tumorigenicity in orthotropic GBM mouse model, compared to parent cells. Furthermore, recurrent cells exhibited elevated velocity irrespective of substrate stiffness, which indicated that recurrent cells may possess inherent differential mechanosignalling ability which was reflected by higher expression of ECM proteins like Collagen IVA, MMP2 and MMP9. Moreover, mice brain injected with recurrent cells grown on 0.5kPa substrate showed higher Young’s modulus values suggesting that recurrent cells conditioned on 0.5kPa make the surrounding ECM stiffer. Importantly, inhibition of EGFR signaling, that is amplified with tissue stiffening in GBM resulted in decreased invasion, migration and proliferation in 0.5kPa recurrent cells, but interestingly survival remained unaffected, highlighting the importance of mimicking the physiological stiffness of the brain mimicking clinical scenario. Total RNA seq analysis of parent and recurrent cells grown on plastic and 0.5kPa substrate identified PLEKHA7 as significantly upregulated gene specifically in 0.5kPa recurrent sample. Higher protein expression of PLEKHA7 in recurrent GBM as compared to primary GBM was validated in patient biopsies. Accordingly, PLEKHA7 knockdown reduced invasion and survival of recurrent GBM cells. Together, these data provides a model system that captures the differential mechanosensing signals of primary and recurrent GBM cells and identifies a novel potential target specific for recurrent GBM.

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

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