Investigating the role of RUNX2 activation across cancer evolution in lung adenocarcinoma

研究 RUNX2 激活在肺腺癌癌症进化过程中的作用

• 批准号: 10683738
• 负责人: Lindsay Marie LaFave
• 金额: $ 19.44万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683738
• 关键词: Address; Advisory Committees; Binding; Cancer Biology; Cancer Etiology; Cell Line; Cell secretion; Cells; Cessation of life; Chromatin; Chromatin Structure; Communication; Data; Dependence; Development; Disease; Eligibility Determination; Engineering; Enhancers; Epigenetic Process; Event; Evolution; Exhibits; Extracellular Matrix; Gene Abnormality; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genetically Engineered Mouse; Goals; Grant; Heterogeneity; Histologic; Histones; Homeostasis; Human; Immune; Immunoprecipitation; Institution; Intervention; Investigation; KRASG12D; Knock-out; Lung Adenocarcinoma; Malignant Neoplasms; Maps; Mediating; Mentorship; Modeling; Mutation; Normal tissue morphology; Oncogenes; Oncogenic; Organoids; Patient-Focused Outcomes; Patients; Population; Positioning Attribute; Postdoctoral Fellow; Regulator Genes; Reproducibility; Research; Research Ethics; Resources; Role; Sampling; Secure; Series; Shapes; Slide; Somatic Mutation; Stromal Neoplasm; System; TP53 gene; Technology; Therapeutic; Tissues; Training; Training Activity; Transcriptional Activation; Tumor stage; Tumor-Derived; Work; cancer cell; cancer initiation; career development; chromatin remodeling; cofactor; driver mutation; epigenomics; experimental study; extracellular; genome-wide; graduate school; human disease; in vivo; mouse model; neoplastic cell; novel; overexpression; patient subsets; post-doctoral training; programs; skills; targeted treatment; transcription factor; tumor; tumor heterogeneity; tumor initiation; tumor microenvironment; tumor progression

Project Summary Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related death; however, only a subset of patients are eligible for targeted therapies based on the presence of mutations in certain oncogenic drivers. In addition, many therapeutic approaches target cancer-initiating events, yet tumor cells acquire alternative dependencies during tumor progression. In this proposal, I aim to interrogate tumor progression in a genetically engineered mouse (GEM) model of lung adenocarcinoma termed the KP (KrasG12D/+; p53f/f) model, which faithfully recapitulates features of human disease. Transcriptional dysregulation occurs across KP tumor progression and is not explained by the acquisition of somatic mutations, suggesting that tumor evolution is driven predominantly by epigenetic mechanisms. In previous work leveraging single-cell chromatin profiling, I determined that KP tumors were marked by substantial epigenetic intratumoral heterogeneity. Interestingly, I found that late-stage populations of tumor cells exhibited progressive activation of RUNX2 transcriptional activity. In addition, RUNX2 activated cells have increased chromatin accessibility surrounding genes involved in extracellular secretion; however, the mechanism(s) by which RUNX2 alters chromatin state and gene expression programs is not well-established. Based on this and other data, my central hypothesis is that RUNX2 functions as a master regulatory transcription factor during late-stage tumor progression that aberrantly initiates gene programs that serve to i) reshape the local tumor microenvironment, ii) facilitate differential stromal/immune composition, and iii) contribute to increased intratumoral heterogeneity. My first aim will interrogate the global chromatin changes and identify RUNX2-associated cofactors in RUNX2- activated cells. The second aim will specifically focus on the role of RUNX2 activation on the remodeling of the local tumor microenvironment. The third aim will more broadly assess the spatial localization of heterogeneous gene expression programs in late-stage cancer cells. This proposal seeks to build on results generated during my postdoctoral training and will serve as the initial focus of my independent research group. My background in cancer biology and epigenetics from my graduate school training, paired with my extensive expertise in GEM models and epigenomic technologies from my postdoctoral training, positions me for a successful transition to independence. As part of this grant, I will assemble an advisory team at my institution to support my transition and career development training activities outlined in this proposal. I will take advantage of the varied resources at my postdoctoral institutions and the institution where I secure an independent position to develop skills related to mentorship, communication, and research ethics. Overall, the outlined training plain in this proposal will greatly support my continued development, with the goal of making substantial contributions in the fields of epigenetics and cancer biology.

项目摘要 肺腺癌（LUAD）是癌症相关死亡的主要原因之一;然而，只有一个子集， 基于某些致癌驱动因子中突变的存在，患者有资格接受靶向治疗。在 此外，许多治疗方法靶向癌症起始事件，但肿瘤细胞获得替代治疗。 肿瘤进展过程中的依赖性。在这个建议中，我的目标是在一个基因上询问肿瘤的进展， 肺腺癌的基因工程小鼠（GEM）模型称为KP（KrasG 12 D/+; p53 f/f）模型， 忠实地再现了人类疾病的特征。在KP肿瘤中发生转录失调 进展，不能用获得体细胞突变来解释，这表明肿瘤的演变是 主要由表观遗传机制驱动。在以前利用单细胞染色质分析的工作中，我 确定KP肿瘤以大量的表观遗传肿瘤内异质性为标志。有趣的是，我 发现晚期肿瘤细胞群体表现出RUNX 2转录的进行性激活， 活动此外，RUNX 2激活的细胞增加了相关基因周围的染色质可及性， 然而，RUNX 2改变染色质状态和基因表达的机制， 表达程序尚未完善。基于这些数据和其他数据，我的核心假设是， RUNX 2在晚期肿瘤进展中作为主要的调节转录因子发挥作用， 异常启动基因程序，用于i）重塑局部肿瘤微环境，ii）促进 差异性基质/免疫组成，和iii）有助于增加肿瘤内异质性。我的第一 目的是询问整体染色质变化，并确定RUNX 2相关的辅因子， 激活细胞第二个目标将特别关注RUNX 2激活对重塑的作用。 局部肿瘤微环境。第三个目标将更广泛地评估 晚期癌细胞中的异质基因表达程序。这项建议力求以成果为基础， 在我的博士后培训期间产生，并将作为我的独立研究小组的最初重点。 我在研究生院接受的癌症生物学和表观遗传学方面的背景， 我的博士后培训在GEM模型和表观基因组技术方面的专业知识，使我成为一个 成功过渡到独立。作为这笔赠款的一部分，我将在我的机构组建一个咨询团队， 支持本建议书中概述的过渡和职业发展培训活动。我带 我的博士后机构和我获得博士学位的机构的各种资源的优势 独立的立场，发展有关的指导，沟通和研究道德的技能。总体看 本建议书中概述的培训内容将极大地支持我的持续发展，目标是使 在表观遗传学和癌症生物学领域的重大贡献。