Investigating the molecular and cellular mechanisms of virus-associated hepatocellular carcinoma

研究病毒相关性肝细胞癌的分子和细胞机制

基本信息

批准号：
10651902
负责人：
HSUAN-AN CHEN
金额：
$ 9.83万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651902
关键词：
ATAC-seq Address Advanced Malignant Neoplasm Alleles Antigen Presentation Antigen Presentation Pathway Automobile Driving Biological Phenomena Biology Bypass Cancer Control Cancer Etiology Cancer Patient Cell Aging Cell Communication Cell Cycle Arrest Cell Surface Proteins Cell surface Cells Characteristics Cues Data Development Disease Disease Outbreaks Engineering Environment Epigenetic Process Epithelium Evolution Extrahepatic Genetic Genetic Screening Goals Heterogeneity Immune Immune Evasion Immune system Immunity Immunocompetent Immunocompromised Host Immunodeficient Mouse Immunologic Surveillance Immunology Immunotherapy Impairment Knock-in Mouse Label Laboratories Lesion Ligands Link Liver neoplasms Lung Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of liver Mass Spectrum Analysis Mediating Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Modeling Molecular Mouse Strains Mus Natural Immunity Natural Killer Cells Neoplasm Metastasis Pathway interactions Patients Phase Play Population Heterogeneity Postdoctoral Fellow Predisposition Primary carcinoma of the liver cells Process Proliferating Proteome Regulatory Pathway Research Research Project Grants Role Shapes Side Site TP53 gene Technology Tumor Immunity Tumor Promotion Validation Virus Work adaptive immunity anti-tumor immune response cancer cell cancer therapy cell injury dynamical evolution exhaustion immune clearance immunoregulation in vivo insight molecular dynamics mortality mouse model neoplastic cell novel novel strategies pharmacologic programs restoration senescence single-cell RNA sequencing tool transcriptome sequencing tumor tumor initiation tumor progression tumor-immune system interactions tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Cancer development accompanies with the dynamic evolution of immunity, a well-known process termed as immunoediting. However, the underlying mechanisms of the transition between each phase, from immune surveillance to final escape, still remain a lot to discover. This proposal aims to study immunoediting during liver cancer development and progression, with a focus on senescence and metastasis. Senescence is a cell cycle arrest program that limits the expansion of damaged cells and can trigger anti-tumor immunity that leads to their elimination in vivo, serving as a potent barrier to tumorigenesis. However, during tumor initiation, the effective clearance of senescent cells is compromised, warranting a deeper mechanistic understanding of this process. My doctoral research aims to identify critical molecular and cellular players driving anti-tumor immune responses during senescence surveillance triggered by wildtype p53, which is known to modulates cancer immunity. The long-term objective of my thesis project is to define the mechanisms of how senescent cells are susceptible to immune surveillance and how these mechanisms are evaded or bypassed during cancer development and progression. As described in Specific Aims 1.1-1.3, my thesis work has demonstrated that the p53 restoration triggers regression of liver cancers in an immunocompetent host. Using different immunodeficient mouse strains and pharmacological approaches perturbing specific immune compartments, our preliminary data suggests that adaptive immunity plays a key role in senescence surveillance. RNA-seq and mass spectrometry were conducted on both proliferating and senescent tumor cells and revealed several senescence-enriched cell surface factors related to epithelial-immune cell interactions. In Specific Aims 1.4 and 1.5, we aim to functionally interrogate the role of these senescence-induced factors as novel senescence surveillance effectors, with a focus on the regulatory network of antigen presentation pathway and, by exploiting multiplexed in vivo genetic screens established in the Lowe laboratory. My postdoctoral research will continue to study immunoediting with a slight change of the focus from the epithelial-tumor angle to a more immunology-rich perspective, applied to the problem of metastatic immune escape. The proposal aims to investigate the molecular changes of NK cells, shown to have control of early metastasis, after having physical interaction with metastatic cells. During different stages of metastatic colonization, tumor-engaging NK cells are labeled via “SynNotch” technology and will be subjected to single-cell RNA-seq to unveil the NK cell heterogeneity (Specific Aim 2.1) and ATAC-seq to reveal potential epigenetic mechanisms of immune exhaustion with functional perturbation of the altered programs employed (Specific Aim 2.2). The proposed postdoctoral research will increase our mechanistic understanding of NK biology during the metastasis outbreak, paving new paths to harness innate immunity against cancer. In all, these two projects will offer distinct insight into immunoediting, of which the elucidated mechanisms could be exploited for developing novel immunotherapies, jointly with existing ones for more effective cancer control.

项目概要/摘要癌症的发展伴随着免疫的动态进化，这是一个众所周知的过程，称为然而，每个阶段之间过渡的潜在机制来自免疫。监视到最终逃脱，仍有很多有待发现。该提案旨在研究肝脏期间的免疫编辑。癌症的发展和进展，重点是衰老和转移。衰老是一个细胞周期。抑制程序可以限制受损细胞的扩张，并可以触发抗肿瘤免疫，从而导致它们体内消除，作为肿瘤发生的有效屏障，然而，在肿瘤发生过程中，有效的。衰老细胞的清除受到影响，需要对这一过程有更深入的机械理解。我的博士研究旨在识别驱动抗肿瘤免疫反应的关键分子和细胞参与者衰老过程中由野生型 p53 触发，众所周知，p53 可以调节癌症免疫。我的论文项目的长期目标是确定衰老细胞如何容易受到影响的机制免疫监视以及这些机制在癌症发展过程中如何被逃避或绕过正如具体目标 1.1-1.3 中所述，我的论文工作证明了 p53 的恢复。使用不同的免疫缺陷小鼠品系触发免疫功能正常宿主的肝癌消退。和药理学方法扰乱特定的免疫区室，我们的初步数据表明适应性免疫在RNA-seq和质谱分析中发挥着关键作用。对增殖和衰老的肿瘤细胞进行研究，发现了几种富含衰老的细胞在具体目标 1.4 和 1.5 中，我们的目标是在功能上研究与上皮-免疫细胞相互作用相关的表面因素。询问这些衰老诱导因子作为新型衰老监视效应器的作用，专注于抗原呈递途径的调控网络，并通过利用多重体内遗传我的博士后研究将继续研究免疫编辑。将焦点从上皮肿瘤角度稍微改变到更丰富的免疫学视角，应用于该提案旨在研究NK细胞的分子变化，在不同时期与转移细胞发生物理相互作用后，显示出对早期转移的控制。在转移定植阶段，肿瘤参与的 NK 细胞通过“SynNotch”技术进行标记，并将被进行单细胞 RNA-seq 揭示 NK 细胞异质性（具体目标 2.1）和 ATAC-seq 揭示免疫耗竭与程序功能扰动的潜在表观遗传机制就业（具体目标 2.2）。拟议的博士后研究将增加我们的机制理解 NK 生物学在转移爆发期间的研究，为利用先天免疫对抗癌症铺平了新的道路。总之，这两个项目将为免疫编辑提供独特的见解，并阐明其中的机制。用于开发新型免疫疗法，与现有疗法联合使用，以更有效地控制癌症。