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：
10608218
负责人：
HSUAN-AN CHEN
金额：
$ 9.5万
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/10608218
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 Epithelial 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 Lead 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 Pharmacology Phase Play Population Heterogeneity Primary carcinoma of the liver cells Process Proliferating Proteome Regulatory Pathway Research Research Project Grants Role Shapes Side Site TP53 gene Technology Tumor Immunity Validation Virus Work adaptive immunity anti-tumor immune response base cancer cell cancer therapy cell injury dynamical evolution exhaustion immune clearance immunoregulation in vivo insight mortality mouse model neoplastic cell novel novel strategies 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.

项目摘要/摘要癌症发展伴随免疫的动态演变，这是一个称为著名的过程但是，免疫程序。最终逃生的监视仍然很多。癌症的发展和进展，重点是鼻子和转移。限制损坏细胞的逮捕程序，并可能触发抗肿瘤的侵害。在体内消除，是肿瘤发生的斑点障碍。衰老细胞的清除受到损害，需要对此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玩家在衰老期间，野生型p53触发了癌症我的论文项目的长期目标是定义衰老细胞如何容易受到的机制免疫监视以及如何在癌症发展和进展。使用不同的免疫缺陷型小鼠菌株在免疫能力宿主中触发肝癌的回归。和药理学方法扰乱了特定的免疫室，我们的初步数据表明，自适应免疫在衰老中起关键作用。在增殖和衰老的肿瘤细胞上进行，并揭示了衰老的细胞严格表面因子与特定目的1.4和1.5的上皮 - 免疫细胞相互作用有关询问theSencencE诱导的因子作为新型衰老爆发效应子的作用，专注于抗原表现途径的监管网络和在Lowe实验室中建立的屏幕。焦点从上皮肿瘤的角度变为更含糊的视角，应用于转移性免疫逃脱的问题旨在研究NK细胞的分子变化在与转移细胞的物理相互作用之后，显示出对早期转移的控制转移性定殖，肿瘤吸引NK细胞的阶段通过“同步”技术标记，将是受到单细胞RNA-Seq的影响，以揭示NK细胞异质性（特定目标2.1）和ATAC-SEQ以揭示免疫疲劳的潜在表观遗传机制，其功能扰动的变化程序使用（特定目标2.2）。在转移爆发期间的NK生物学，铺平了新的途径，以利用先天性免疫所有这些项目都将为免疫编辑而定，阐明机制可能是开发用于开发新型免疫疗法的，共同与现有的免疫疗法共同进行，以更有效地控制癌症。