Matrix in pre-cirrhotic HCC

肝硬化前 HCC 的基质

• 批准号: 10578389
• 负责人: Natalie J. Torok
• 金额: $ 57.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578389
• 关键词: 3-Dimensional; Acceleration; Address; Advanced Glycosylation End Products; Affect; Amino Acids; Animal Model; Architecture; Behavior; Cells; Cirrhosis; Clinical; Collagen; Data; Deposition; Diet; Disease Progression; Down-Regulation; Elasticity; Embryo; Environment; Epidemic; Exhibits; Future; Hepatocyte; Human; Hydrogels; Incidence; Injections; Injury; Invaded; Lead; Link; Liver; Malignant Neoplasms; Mediating; Modeling; Mus; Neoplasm Metastasis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathway interactions; Patients; Phenotype; Prevalence; Primary carcinoma of the liver cells; Production; Proliferating; Property; Proteoglycan; Pyridoxamine; Relaxation; Risk Factors; Signal Transduction; Stress; System; Techniques; Testing; Therapeutic; Time; Tissues; Tumor Burden; Viscosity; Work; beta catenin; cancer cell; carcinogenicity; cell behavior; cell motility; cell transformation; crosslink; diabetic; glycemic control; improved; in vitro Model; in vivo; in vivo Model; inhibitor; liver cancer model; liver injury; migration; mutant; nonalcoholic steatohepatitis; novel; permissiveness; receptor; receptor for advanced glycation endproducts; response; sex; tensin; three-dimensional modeling; transcriptome sequencing; translational study; tumor; viscoelasticity

Project Summary/Abstract Non-alcoholic steatohepatitis (NASH) is a major cause of HCC. It is clinically recognized that HCC in NASH often arises at a pre-cirrhotic stage, however the pathomechanism of HCC in non-cirrhotic livers is not well understood. As T2DM with poor glycemic control is an independent risk factor for HCC it is plausible that there are distinct pathways that create a pro- carcinogenic niche in non-cirrhotic T2DM/NASH. We showed that the accumulation of advanced glycation end products (AGEs) in patients with T2DM/NASH and in an animal model are key to necroinflammation and oxidative liver injury. Downregulation of the AGE clearance receptor AGER1 accelerated AGE deposition, and correcting AGER1 in vivo improved NASH. To study how high AGE environment creates permissive conditions for transformed cells, we modulated diet/AGE content prior to hydrodynamic injection of hMET/mutant β-catenin: 1) High AGE background induced an earlier and more invasive HCC, 2) AGE accumulation was linked to significant changes in matrix dynamics-with an increase in energy dissipation or loss and faster stress relaxation in response to a deformation - in an AGE and receptor for AGEs (RAGE)-dependent manner, 3) Inhibiting AGE production reversed changes in matrix viscoelasticity in vivo and lowered tumor burden. We will test the hypothesis that in non- cirrhotic T2DM/NASH accumulation of AGEs contribute to an increase in matrix viscoelasticity and matricellular changes creating a pro-invasive environment. Aim 1: We propose to investigate the link between diet/AGE content, matrix viscoelasticity, sex and HCC phenotypes and outcomes in a novel HCC model. In particular we will focus on how AGE-mediated collagen crosslinks on specific amino acids can alter intermolecular recognition and interaction with proteoglycans thereby affecting matrix dynamics. Aim 2: We will dissect the effects of RAGE and AGER1 signals and AGE accumulation on matrix viscoelastic parameters and HCC phenotypes. In Aim 3 we propose to develop a 3D hydrogel system with tunable viscoelasticity and the impact of AGEs-modified matrix on cell behavior will be studied. Based on the RNAseq data we will focus on the pathomechanism of how viscoelastic changes are sensed by cells, and the key matricellular signals that confer invasive and migratory properties. These studies will demonstrate the impact of AGEs on the liver matrix in non-cirrhotic NASH and outline the pathomechanism for a pro-invasive environment. Defining the key matricellular signals that drive invasion will enable us to pursue translational studied in the future.

项目总结/摘要 非酒精性脂肪性肝炎（NASH）是HCC的主要原因。临床上公认， NASH中的HCC通常发生在癌前阶段，然而，NASH中HCC的病理机制并不清楚。 对非肝病肝脏的认识还不太清楚。由于血糖控制不佳的T2 DM是一种 HCC的独立危险因素，似乎有不同的途径产生促癌细胞增殖， 在非糖尿病性T2 DM/NASH中的致癌生态位。我们发现， T2 DM/NASH患者和动物模型中的晚期糖基化终末产物（AGEs） 是坏死性炎症和氧化性肝损伤的关键。AGE清除率下调 受体AGER 1促进AGE沉积，在体内纠正AGER 1可改善NASH。 为了研究高AGE环境如何为转化细胞创造允许条件，我们 在流体动力学注射hMET/突变体β-连环蛋白之前调节的饮食/AGE含量： AGE背景诱导早期和更具侵袭性的HCC，2）AGE积累与 基质动力学的显著变化-能量耗散或损失增加， 在AGE和AGEs受体中，对变形的响应更快的应力松弛 （3）抑制AGE的产生逆转了基质的变化 体内粘弹性和降低的肿瘤负荷。我们将测试假设，在非- AGEs的代谢性T2 DM/NASH积累有助于基质粘弹性的增加 和基质细胞的变化创造了一个有利于侵入的环境。目标1：我们建议 调查饮食/AGE含量、基质粘弹性、性别和HCC表型之间的联系 和新的HCC模型的结果。特别是，我们将重点关注AGE介导的 特定氨基酸上的胶原交联可以改变分子间的识别和相互作用 从而影响基质动力学。目标2：我们将剖析 基质粘弹性参数和HCC上的AGER和AGER 1信号和AGE累积 表型在目标3中，我们提出开发具有可调粘弹性的3D水凝胶系统 并研究AGEs修饰基质对细胞行为的影响。基于RNAseq 数据我们将重点关注细胞如何感知粘弹性变化的病理机制，以及 赋予侵入性和迁移性的关键基质细胞信号。 这些研究将证明AGEs对非酒精性NASH患者肝脏基质的影响。 并勾勒出一个亲侵入环境的病理机制。定义关键的细胞基质 驱动入侵的信号将使我们能够在未来进行翻译研究。