Interferon regulation by NBR1-driven chaperone-mediated autophagy in stellate cells in liver cancer

NBR1驱动的伴侣介导的肝癌星状细胞自噬对干扰素的调节

• 批准号: 10533345
• 负责人: Jorge Moscat
• 金额: $ 48.79万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10533345
• 关键词: Ablation; Address; Agonist; Autophagocytosis; Biological Markers; CD8-Positive T-Lymphocytes; Cells; Chronic; Complex; Data; Data Set; Defect; Development; Fibrosis; Genetic; Goals; Hepatic Stellate Cell; Hepatocarcinogenesis; Hepatocyte; Human; Immune; Immune system; Immunologic Surveillance; Immunosuppression; Impairment; In Vitro; Inflammation; Inflammatory; Innovative Therapy; Interferon Activation; Interferons; Knowledge; Laboratories; Liver; Liver Fibrosis; Liver neoplasms; Malignant neoplasm of liver; Mediating; Molecular; Molecular Chaperones; Mus; Mutation; Oncogenes; Pathway interactions; Patients; Play; Population; Prevention; Primary carcinoma of the liver cells; Process; Proteins; Proteomics; Publishing; Regulation; Reporter; Repression; Role; Signal Pathway; Signal Transduction; Therapeutic; Tumor Promotion; Up-Regulation; design; effective therapy; experimental study; human data; in vivo; liver inflammation; member; neoplastic cell; new therapeutic target; novel; programs; response; restraint; scaffold; stellate cell; targeted treatment; treatment response; tumor; tumor heterogeneity; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

PROJECT SUMMARY The long-term goal of this proposal is to understand the molecular and cellular mechanisms in the tumor microenvironment that govern hepatocellular carcinoma (HCC) development, with a special focus on the role of hepatic stellate cells (HSCs) as central players in this process. While it is clear that activation of non-parenchymal cells is a key contributor to liver tumorigenesis, unfortunately, our knowledge of the molecular mechanisms whereby key stromal and immune cell populations regulated HCC initiation and progression still is fragmentary. Activated HSCs are key contributors to liver fibrosis and inflammation. The present proposal is based on our previously published results demonstrating that the autophagy and signaling adaptor p62 is reduced in HSCs from HCC patients and that its inactivation in mice, either globally or HSC-specific, promoted HCC due to the hyperactivation of the inflammatory and fibrotic activities of HSCs. Our new unpublished preliminary results demonstrate that the genetic ablation of NBR1, either globally or selectively in HSCs, completely reverts the pro- tumorigenic role of p62 deficiency in HSCs. However, this unexpected effect of NBR1 deficiency does not revert the pro-fibrotic, TGFb-driven effect of p62 loss and did not affect autophagy but resulted in the hyperactivation of the interferon (IFN) cascade that renders CD8+ T cells more active, increasing anti-tumor immunosurveillance. Our preliminary data also suggest that this hyperactivation of the IFN pathways is due to impaired chaperone- mediated autophagy (CMA). Therefore, in this proposal we intend to unravel the mechanisms whereby NBR1 promotes CMA to restrain IFN activation. We will also establish how reduced CMA due to the inactivation of NBR1 in HSCs results in the reprograming of the tumor microenvironment to repress tumorigenesis. To that end, we will build on our preliminary data to address the following critical questions: (Aim 1) Establish the molecular mechanisms whereby NBR1 regulates the IFN response in HSCs by (Aim 1.1) determining the effect of NBR1 and p62 inactivation on CMA activity in HSCs; (Aim 1.2) determining the functional contribution of CMA to NBR1- mediated IFN regulation in HSCs; and (Aim 1.3) determining the molecular mechanisms whereby NBR1 regulates CMA. We will also (Aim 2) establish the contribution of NBR1 to HSC activation and the creation of a tumor-suppressive microenvironment by (Aim 2.1) determining the impact that NBR1 deletion in HSCs has in the tumor microenvironment of HCC; (Aim 2.2) determining the functional contribution of the CMA-STING-IFN axis in NBR1-deficient HSCs to HCC progression in vivo; and (Aim 2.3) determining the impact of NBR1 loss in HSCs in therapy response and its relevance in human HCC. Results from these studies will serve to identify new biomarkers as well as non-parenchymal new therapeutic targets for the prevention and treatment of HCC.

项目概要 该提案的长期目标是了解肿瘤中的分子和细胞机制 控制肝细胞癌 (HCC) 发展的微环境，特别关注 肝星状细胞（HSC）是这一过程的核心参与者。虽然很明显非实质细胞的激活 细胞是肝脏肿瘤发生的关键因素，不幸的是，我们对分子机制的了解 关键基质细胞和免疫细胞群调节 HCC 发生和进展的机制仍然不完整。 活化的 HSC 是肝纤维化和炎症的关键因素。目前的建议是基于我们的 先前发表的结果表明 HSC 中的自噬和信号转导接头 p62 减少 来自 HCC 患者的 HCC 失活，无论是整体失活还是 HSC 特异性失活，都会促进 HCC，因为 HSC 的炎症和纤维化活性过度激活。我们新的未发表的初步结果 证明 NBR1 的基因消除，无论是在 HSC 中全局还是选择性地消除，都可以完全恢复亲 HSC 中 p62 缺陷的致瘤作用。然而，NBR1 缺陷的这种意想不到的影响不会恢复 p62 缺失的促纤维化、TGFb 驱动作用，不影响自噬，但导致过度激活 干扰素 (IFN) 级联反应使 CD8+ T 细胞更加活跃，增强抗肿瘤免疫监视。 我们的初步数据还表明，干扰素通路的过度激活是由于伴侣蛋白受损所致。 介导的自噬（CMA）。因此，在本提案中，我们打算揭示 NBR1 的机制 促进 CMA 抑制 IFN 激活。我们还将确定由于失活而导致的 CMA 如何降低 HSC 中的 NBR1 会导致肿瘤微环境重新编程，从而抑制肿瘤发生。为此， 我们将在初步数据的基础上解决以下关键问题：（目标 1）建立分子 NBR1 通过（目标 1.1）确定 NBR1 的作用来调节 HSC 中 IFN 反应的机制 p62 失活对 HSC 中 CMA 活性的影响； （目标 1.2）确定 CMA 对 NBR1- 的功能贡献 HSC 中介导的 IFN 调节； （目标 1.3）确定 NBR1 的分子机制 监管 CMA。我们还将（目标 2）确定 NBR1 对 HSC 激活的贡献以及创建 通过（目标 2.1）确定 HSC 中 NBR1 缺失对肿瘤抑制微环境的影响 HCC的肿瘤微环境； （目标 2.2）确定 CMA-STING-IFN 的功能贡献 体内 NBR1 缺陷型 HSC 至 HCC 进展的轴； （目标 2.3）确定 NBR1 损失的影响 HSC 的治疗反应及其与人类 HCC 的相关性。这些研究的结果将有助于确定新的 预防和治疗 HCC 的生物标志物以及非实质新治疗靶点。