Dissecting mechanisms of inflammation driven cancer susceptibility in epithelial barrier tissues

剖析上皮屏障组织中炎症驱动的癌症易感性机制

• 批准号: 10818671
• 负责人: Christopher Cowley
• 金额: $ 8.92万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 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 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818671
• 关键词: Acceleration; Acute; Address; Affect; Award; Binding; Cancer Biology; Cancer Model; Carcinoma; Cell physiology; Cells; Chromatin; Chronic Disease; Classification; Colitis; Colitis associated colorectal cancer; Colon; Colorectal Cancer; Complex; Coupled; Development; Disease Progression; Disease model; Disseminated Malignant Neoplasm; Enhancers; Epigenetic Process; Epithelium; Event; Exposure to; Family; Genes; Genetic Diseases; Genetic Screening; Genomics; Goals; Head; Homeostasis; Human; Immunology; Inflammation; Inflammatory; Inflammatory Response; Institution; Lead; Life; Long-Term Effects; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Memory; Modeling; Molecular; Molecular Biology; Mus; Mutation; Natural regeneration; Oncogenic; Organoids; Papilloma; Pathogenesis; Pathway interactions; Patients; Phase; Physiological; Play; Postdoctoral Fellow; Predisposition; Recurrence; Regenerative capacity; Research; Resolution; Risk; Risk Factors; Role; STAT3 gene; Shapes; Signal Pathway; Skin; Skin Carcinogenesis; Specialized Epithelial Cell; Squamous cell carcinoma; Stimulus; Stress; Students; System; Technical Expertise; Techniques; Tissues; Training; Transcription Factor AP-1; Transforming Growth Factor beta; Tumor Burden; Work; activating transcription factor 3; anticancer research; biological adaptation to stress; chromatin remodeling; cytokine; effective therapy; epigenetic memory; epigenome; epigenomics; epithelial stem cell; experience; histone modification; human disease; in vivo; inflammatory milieu; insight; jun Oncogene; member; mouse genetics; novel; novel strategies; premature; prevent; professor; progenitor; recruit; regeneration potential; restoration; stem; stem cell biology; stem cell population; stem cells; stressor; tissue stem cells; transcription factor; transcriptomics; tumor; tumorigenesis; wound healing

Project Summary/Abstract: Inflammation has long been known to increase risk of tumorigenesis. Epithelial barrier tissues are perpetually exposed to a myriad of environmental and inflammatory insults that necessitates robust regenerative capacity of their tissue-specific epithelial stem cells (EpSCs) to restore barrier integrity. The long term consequences of these inflammatory encounters on the tissue and EpSCs is poorly understood. Here, I seek to understand how exposure to inflammation results in epigenetic and cellular rewiring of EpSCs and their lineages in different barrier tissues and how this rewiring can be maladaptive leading to increased cancer susceptibility. The F99 phase of this proposal is focused on the mechanisms by which inflammatory experience is encoded within the chromatin of skin epithelial stem cells (EpSCs) and how inflammation-experienced skin accelerates tumor formation. I have begun to uncover the molecular mechanisms of how EpSCs acquire and maintain chromatin accessibility at key domains associated with stress response genes that contribute to an inflammatory response. My studies suggest that this phenomenon occurs through the complex and dynamic interplay between transcription factors (TFs) that are naturally present in steady state EpSCs but cannot gain access to stress response enhancers without inflammation-induced TFs. As I unearth the molecular mechanisms involved, I will interrogate how this inflammatory rewiring of skin EpSCs epigenome accelerates tumor formation as EpSCs acquire oncogenic mutations that lead to squamous cell carcinomas (SCCs), a life-threatening, metastatic cancer for which there are few effective therapies. At the completion of the F99 phase, l will have gained strong experience in in vivo high-throughput epigenetics, mouse genetics and epithelial stem cell biology, and transition to a postdoc to gain advanced expertise and training in human cancer and immunology. For the K00 phase, I will shift my focus to how inflammatory experience can reshape colonic epithelium composition in the gut and how this reshaping, along with EpSC epigenetic rewiring, results in colorectal cancer (CRC). Interestingly, colitis can result in colitis-induced CRC that follows a different molecular driven pathogenesis than traditional CRC. Thus, to further understand the mechanisms that drive colitis-induced CRC, I plan to expand my technical expertise to include colitis-induced CRC modeling, single-cell epigenomic and transcriptomic techniques, genetic screening and human organoid modeling. These new approaches coupled with my already strong background in molecular biology and high-throughput genomic analyses, will allow me to address the most pressing and challenging issues in inflammation experience and cancer biology today. With the aid of this award, I intend to continue my research contribution and gain the necessary experience to become an Assistant Professor at a major academic institution. There I will head my own lab and guide my students in epithelial cancer research with the ultimate goal of finding new targets to treat these aggressive cancers.

项目摘要/摘要： 众所周知，炎症会增加肿瘤发生的风险。上皮屏障组织是 永久暴露于无数的环境和炎症性侮辱，需要强大的再生 其组织特异性上皮干细胞（EPSC）的能力恢复屏障完整性。长期 这些在组织和EPSC上的炎症遭遇的后果知之甚少。在这里，我试图 了解暴露于炎症是如何导致EPSC及其血统的表观遗传和细胞重新布线 在不同的屏障组织中，这种重新布线如何适应不良，从而导致癌症的敏感性提高。 该提案的F99阶段的重点是炎症经验的机制 在皮肤上皮干细胞（EPSC）的染色质中编码以及炎症经验的皮肤如何 加速肿瘤形成。我已经开始揭示EPSC如何获得和 在与压力反应基因相关的关键域保持染色质访问性，这有助于 炎症反应。我的研究表明，这种现象是通过复杂而动态的 自然存在于稳态EPSC中但无法获得的转录因子（TF）之间的相互作用 访问没有炎症引起的TF的压力反应增强子。当我发掘分子机制时 涉及，我将询问这种炎症性皮肤EPSC的重新布置如何加速肿瘤形成 由于EPSC获得了导致鳞状细胞癌（SCC）的致癌突变，这是一种威胁生命的 转移性癌症几乎没有有效疗法。在F99阶段完成时，L将有 在体内高通量表观遗传学，小鼠遗传学和上皮干细胞生物学方面获得了丰富的经验， 并过渡到博士后，以获得人类癌症和免疫学方面的高级专业知识和培训。 对于K00阶段，我将把重点转移到炎症体验如何重塑结肠上皮 肠道中的组成以及这种重塑以及EPSC表观遗传重新布线如何导致结直肠癌 （CRC）。有趣的是，结肠炎可能导致结肠炎引起的CRC，后者遵循不同的分子驱动 发病机理比传统CRC。因此，为了进一步了解驱动结肠炎引起的CRC的机制， 我计划将技术专长扩展到包括结肠炎引起的CRC建模，单细胞表观基因组和 转录组技术，基因筛查和人体器官建模。这些新方法耦合 凭借我在分子生物学和高通量基因组分析方面已经很强的背景，将使我能够 解决当今炎症经验和癌症生物学中最紧迫，最具挑战性的问题。和 该奖项的帮助，我打算继续我的研究贡献，并获得必要的经验以成为 一家主要学术机构的助理教授。在那里我将领导自己的实验室，并指导我的学生 上皮癌症研究的最终目的是寻找新的靶标治疗这些侵略性癌症。