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

• 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
• 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

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.

项目总结 肺癌和胰腺导管腺癌通常在肿瘤进展的很晚阶段被诊断出来，当 他们是最具攻击性的，也是最难治疗的。目前，人们对造成这种现象的特征知之甚少 晚期肿瘤的复杂的肿瘤异质性以及什么因素导致癌症的这种变化 随着时间的推移，细胞状态和疾病进展。调查这些贡献的机制如何 影响肿瘤发生的因素和肿瘤的异质性可能揭示未被认识的生物学过程 控制肿瘤的发展。这项工作的目标是阐明分子和细胞机制 推动染色质状态和免疫反应的变化，以及它们如何形成肿瘤的异质性和肿瘤 进步。在F99阶段，我的目标是阐明一种新的肿瘤抑制基因是如何抑制肺的 肿瘤发生学。我和我的同事在一只转基因小鼠身上发现STAG2是一种肿瘤抑制因子 致癌性KRAS驱动的肺癌模型。STAG2是两种主要粘连蛋白复合体之一的亚基， 它们与调节染色质边界和基因表达有关。然而，这一机制通过 目前尚不清楚是哪种STAG2失活导致了肺癌的生长。我做了染色质可及性分析 STAG2熟练表达和STAG2缺陷小鼠肺癌细胞的基因表达分析 STAG2的潜在调节因子发挥作用。根据我的分析，我假设STAG2控制基因 通过直接影响3D染色质组织的粘附素调节参与肿瘤发生的早期阶段。 利用染色质构象分析，我将评估STAG2如何在肿瘤的不同阶段调节染色质 进展和STAG2失活如何推动肺肿瘤的发生。此外，我将使用Tuba-seq来识别 STAG2肿瘤抑制和染色质构象分析的关键上位和下游介质 确定STAG2介导的影响肺癌维持的机制。在K00阶段，我的目标是 阐明癌细胞状态如何影响胰腺导管腺癌对T细胞介导的反应 抗肿瘤免疫。PDAC亚群具有不同的转录特征、基质成分和 以前已经确定了对化疗的反应。然而，目前尚不清楚这些肿瘤是否 亚型对T细胞介导的免疫有不同的反应。为了研究癌细胞状态是如何形成的 PDAC进展通过使细胞毒性T细胞反应得以逃避，我将利用PDAC小鼠模型 使用诱导物在肿瘤进展的不同阶段启动细胞毒性T细胞反应 小鼠模型T细胞抗原。利用纵向多组学、免疫表型和肿瘤体积分析，I 将研究肿瘤异质性如何在不同的免疫逃避机制中发挥作用 肿瘤进展的不同阶段，确定关键的机制驱动因素，从而发现增强抗肿瘤作用的新策略 肿瘤免疫反应。这项工作将共同阐明染色质调节和肿瘤的原理。 促进肺癌和胰腺癌进展和免疫反应的异质性。