Chromatin and immune regulation of tumor growth and progression

肿瘤生长和进展的染色质和免疫调节

基本信息

批准号：
10744436
负责人：
Emily Lorin Ashkin
金额：
$ 4.92万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-10 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744436
关键词：
3-Dimensional Antigens Architecture Bar Codes Biological Assay Biological Process Cells Cellular Immunity Characteristics Chromatin Chromatin Loop Chromosome Mapping Complex Cytotoxic T-Lymphocytes Data Dedications Dependence Development Diagnosis Disease Progression Evolution Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genetically Engineered Mouse Goals Immune Evasion Immune response Immunophenotyping KRAS oncogenesis KRAS2 gene Laboratories Lung Lung Neoplasms Maintenance Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Mediator Mentors Methodology Molecular Molecular Conformation Mus Pancreatic Ductal Adenocarcinoma Phase Play Positioning Attribute Postdoctoral Fellow Proteins Regulation Research Research Project Grants Role Shapes System T cell response T-Lymphocyte Techniques Time Training Tumor Immunity Tumor Subtype Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Tumor Volume Tumor stage Work anti-tumor immune response cancer cell cancer type candidate identification cell type chemotherapy cohesin experience experimental study functional genomics gene function high throughput screening immunoregulation in vivo innovation insight lung cancer cell lung tumorigenesis medical specialties mouse model multidisciplinary multiple omics neoplastic cell novel novel strategies pancreatic ductal adenocarcinoma model response tumor tumor growth tumor heterogeneity tumor immunology tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Lung and pancreatic ductal adenocarcinomas are often diagnosed at very late stages of tumor progression when they are most aggressive and difficult to treat. Currently, very little is known about the characteristics that make up the complex tumor heterogeneity of late-stage tumors and what factors contribute to such changes in cancer cell state and disease progression over time. Investigating how the mechanisms by which these contributing factors impact tumorigenesis and tumor heterogeneity may uncover unappreciated biological processes that control tumor development. The goal of this work is to elucidate the molecular and cellular mechanisms that drive changes in chromatin state and immune response and how they shape tumor heterogeneity and tumor progression. In the F99 phase, I aim to elucidate how a novel tumor suppressor gene constrains lung tumorigenesis. My colleagues and I identified STAG2 as a tumor suppressor in a genetically engineered mouse model of oncogenic KRAS-driven lung cancer. STAG2 is a subunit of one of the two major cohesin complexes, which are implicated in regulating chromatin boundaries and gene expression. However, the mechanism by which Stag2 inactivation drives lung tumor growth is unknown. I performed chromatin accessibility profiling and gene expression analyses on STAG2-proficient and STAG2-deficient mouse lung cancer cells and have unveiled potential mediators of STAG2 function. Based on my analyses, I hypothesize that STAG2 controls genes involved in early stages of tumorigenesis by directly impacting cohesin regulation of 3D chromatin organization. Using chromatin conformation assays, I will assess how STAG2 regulates chromatin at different stages of tumor progression and how Stag2 inactivation drives lung tumorigenesis. Additionally, I will use Tuba-seq to identify key epistatic and downstream mediators of STAG2 tumor suppression and chromatin conformation assays to ascertain the STAG2-mediated mechanisms impacting lung tumor maintenance. In the K00 phase, I aim to elucidate how cancer cell state shapes pancreatic ductal adenocarcinoma (PDAC) response to T-cell mediated anti-tumor immunity. PDAC subpopulations with distinct transcriptional profiles, stromal composition, and response to chemotherapy have been previously established. However, it remains unknown whether these tumor subtypes harbor differential response to T-cell mediated immunity. To investigate how cancer cell state shapes PDAC progression by enabling evasion of cytotoxic T cell responses, I will leverage PDAC mouse models that enable the initiation of cytotoxic T cell responses at different stages of tumor progression using an inducible mouse model T cell antigen. Using longitudinal multi-omics, immunophenotyping, and tumor volume analyses, I will investigate how aspects of tumor heterogeneity contribute to mechanisms of immune evasion at various stages of tumor progression, identify key mechanistic drivers, and thus uncover novel strategies to enhance anti- tumor immune responses. Together, this body of work will elucidate principles of chromatin regulation and tumor heterogeneity that contribute to progression and immune response in lung and pancreas cancers.

项目摘要肺和胰腺导管腺癌通常在肿瘤进展的很晚阶段被诊断他们最具侵略性，难以治疗。目前，关于制造的特征知之甚少加强晚期肿瘤的复杂肿瘤异质性，以及哪些因素导致了癌症的变化随着时间的流逝，细胞状态和疾病进展。调查这些机制如何贡献因素会影响肿瘤发生和肿瘤异质性，可能会发现未欣赏的生物学过程控制肿瘤的发展。这项工作的目的是阐明分子和细胞机制驱动染色质状态和免疫反应的变化以及它们如何塑造肿瘤异质性和肿瘤进展。在F99阶段，我旨在阐明新型肿瘤抑制基因如何约束肺肿瘤发生。我和我的同事将Stag2确定为基因工程小鼠的肿瘤抑制剂致癌KRAS驱动的肺癌的模型。 Stag2是两个主要粘蛋白复合物之一的亚基，这与调节染色质边界和基因表达有关。但是，通过 Stag2灭活驱动肺部肿瘤生长尚不清楚。我进行了染色质访问性分析和基因表达分析了Stag2促进和Stag2缺陷型小鼠肺癌细胞，并已揭幕 Stag2功能的潜在介体。根据我的分析，我假设Stag2控制基因通过直接影响3D染色质组织的粘着蛋白调节，参与肿瘤发生的早期阶段。使用染色质构象测定法，我将评估Stag2如何在肿瘤的不同阶段调节染色质进展以及Stag2灭活如何驱动肺部肿瘤发生。此外，我将使用tuba-seq识别 Stag2肿瘤抑制和染色质构象测定的关键信世和下游介体对确定影响肺部肿瘤维持的Stag2介导的机制。在K00阶段，我的目标是阐明癌细胞状态如何形状胰腺导管腺癌（PDAC）对T细胞介导的反应抗肿瘤免疫。 PDAC亚群具有不同的转录曲线，基质组成和先前已经建立了对化学疗法的反应。但是，这些肿瘤是否尚不清楚亚型具有对T细胞介导的免疫力的不同反应。研究癌细胞状态的形状 PDAC进展通过逃避细胞毒性T细胞反应，我将利用PDAC小鼠模型启动使用诱导的肿瘤进展不同阶段的细胞毒性T细胞反应小鼠模型T细胞抗原。使用纵向多词，免疫表型和肿瘤体积分析，I 将研究肿瘤异质性方面如何有助于各种免疫逃避机制肿瘤进展的阶段，确定关键的机械驱动因素，从而发现了增强抗抗的新型策略肿瘤免疫反应。这项工作将阐明染色质调节和肿瘤的原理有助于肺和胰腺癌进展和免疫反应的异质性。