Diabetes and extracellular matrix in NASH

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Non-alcoholic steatohepatitis (NASH) is a risk factor for hepatocellular carcinoma (HCC) that often arises at a pre-cirrhotic stage. As this patient population is not screened, often these tumors are diagnosed at a late stage. We seek to understand how distinct pathways could create a pro-carcinogenic environment in non-cirrhotic NASH. We previously showed that advanced glycation end products (AGEs) in patients with pre-cirrhotic T2DM/NASH and in an animal model, are key to necroinflammation and oxidative liver injury. The AGE clearance receptor AGER1 was downregulated in NASH, accelerating AGE deposition, and correcting AGER1 in vivo improved liver injury. To study how high AGE environment creates permissive conditions for transformed cells, we modulated the diet/AGE content prior to hydrodynamic injection of hMET/mutant β-catenin. High AGE background induced an earlier and more invasive HCC, and AGE accumulation was linked to significant changes in matrix dynamics. We found that AGE inhibition reversed changes in matrix viscoelasticity in vivo and lowered the tumor burden. We will test the hypothesis that in non-cirrhotic T2DM/NASH AGEs contribute to an increase in matrix viscoelasticity and matricellular changes creating a pro-invasive environment. In Aim 1, we will establish and investigate a novel NASH model to study the association between diet/AGE content, matrix viscoelasticity, gender and HCC characteristics as well as outcomes. In Aim 2 we propose to develop a 3D hydrogel system with tunable viscoelasticity to study cellular shape/cytoskeletal changes, invasion and migration. Using RNAseq data we will explore the key matricellular signals that confer invasive and migratory properties. These studies will for the first time outline how viscoelasticity elicits a pro-invasive niche, and identify the key matricellular signals that drive invasion of HCC.