Mechanisms of Esophageal Carcinogenesis

食管癌发生机制

• 批准号: 10305930
• 负责人: Anil K Rustgi
• 金额: $ 13.81万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2021-07-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305930
• 关键词: 3-Dimensional; Advisory Committees; Affect; Anatomy; Apoptosis; Barrett Esophagus; Behavior; Biological; Biological Models; CCND1 gene; CCNE1 gene; CCR5 gene; CD44 gene; CDK2 gene; CDK4 gene; Cell Cycle; Cells; Chromosomal Instability; Clinical Trials; Combined Modality Therapy; Core Facility; Coupling; Cyclin D1; Cyclins; Cytotoxic T-Lymphocytes; DNA Sequence Alteration; Dependence; Desmoplastic; Dysplasia; Epidermal Growth Factor Receptor; Epigenetic Process; Esophageal Adenocarcinoma; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagus; FXR1 gene; Fibroblasts; Fostering; Genetic; Genetically Engineered Mouse; Genome Stability; Genomics; Glutaminase; Glutamine; Grant; Head and neck structure; Human; Immune; Immune Evasion; Immunotherapy; Individual; Innovative Therapy; Institution; Invaded; Leadership; Lesion; Life Style; Lung; Lung Adenocarcinoma; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediator of activation protein; Metabolism; Molecular; Mus; Neoplasm Metastasis; Organoids; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Pre-Clinical Model; Prognosis; Property; Protein Cycling Pathway; Proteins; Publications; RANTES; RANTES receptor; RNA-Binding Proteins; Reagent; Recycling; Research; Research Personnel; Role; Shapes; Survival Rate; TP53 gene; Therapeutic; Therapeutic Studies; Translating; Tumor Cell Invasion; Xenograft procedure; anti-tumor immune response; cancer cell; cell type; cohesion; cytokine; esophageal carcinogenesis; esophageal squamous cell cancer; genomic aberrations; human tissue; improved; inhibitor/antagonist; innovation; lymph nodes; lymphoid organ; mouse model; mutant; neoplastic cell; novel; novel therapeutic intervention; optimal treatments; overexpression; pre-clinical; preclinical trial; programs; symposium; synergism; therapeutic target; three dimensional cell culture; transcriptome; transcriptome sequencing; transcriptomics; tumor; tumor microenvironment; tumor-immune system interactions; ubiquitin-protein ligase; uptake

PROJECT SUMMARY - OVERALL Esophageal cancer is common worldwide. There are two major subtypes: esophageal squamous cell cancer (ESCC) and esophageal adenocarcinoma (EAC). Precursor lesions include esophageal squamous dysplasia and esophageal intestinal metaplasia (=Barrett's Esophagus), respectively. The molecular pathogenesis of ESCC and EAC involves genomic aberrations (e.g. cyclin D1, cyclin E, epidermal growth factor receptor or EGFR), genetic mutations or loss (e.g. TP53, p120catenin), epigenetic alterations, transcriptome derangements and interplay with environmental/lifestyle variables. As our primary overarching objective, we have made significant progress in this integrated Program Project (P01) to the identification and characterization of mechanisms underlying the molecular pathogenesis of ESCC and EAC as related to genomic and genetic “divers” in tumor cells, novel interactions in the tumor microenvironment and approaches to tumor metastasis. As our secondary overarching objective, we are discovering common principles in biological behavior between the anatomically related ESCC with head/neck SCC and lung SCC as well as EAC with lung adenocarcinoma (LAC). For our third overarching objective, we seek to translate our novel 3D organotypic culture/3D organoid and mouse models, findings in human tissues, and preclinical therapeutic studies to clinical trials in patients. Our integrated and cohesive 3 projects and 3 core facilities, with unequivocal support from our institutions, rigorous review by internal and external advisory boards, have had significant impact upon the field of esophageal cancers and related cancers. Each Project and Core has Specific Aims and Research Strategies that are intertwined through intellectual concepts, model systems/reagents and experimental approaches that would not be possible through individual grants. Pivotal concepts and approaches in this P01 competing renewal relate to cyclin D1/CDK4 and cyclin E deregulation with new therapeutic approaches to CDK4/6 inhibition and the immune microenvironment, CDK2 inhibition (cyclin E kinase partner), and glutaminase inhibition (due to glutamine addition in the face of cyclin D1 overexpression); mutant p53 and its roles in endocytic recycling, tumor invasion and tumor metastasis; and the RANTES cytokine in the tumor microenvironment with therapeutic targeting. Our synergy has resulted in our being highly productive with visible publications, presentations at conferences, influencing the field through expansion of investigators in the field and providing leadership in task forces, which we will augment even more. In aggregate, our integrated and rigorous projects, buttressed by innovative Cores, will shape the landscape in esophageal cancer.

项目摘要 - 总体 食管癌在全球范围很常见。有两个主要亚型：食道鳞状细胞 癌症（ESCC）和食管腺癌（EAC）。前体病变包括食管鳞状 发育不良和食管肠道化生（= Barrett的食道）。分子 ESCC和EAC的发病机理涉及基因组畸变（例如Cyclin D1，Cyclin E，表皮生长 因子受体或EGFR），基因突变或损失（例如TP53，P120卡宁），表观遗传改变， 转录组的演变和与环境/生活方式变量的相互作用。作为我们的主要 总体目标，我们在这个集成的计划项目（P01）中取得了重大进展 ESCC和EAC分子发病机理的基础机制的鉴定和表征 与肿瘤细胞中的基因组和遗传“潜水”有关，肿瘤微环境中的新型相互作用 和肿瘤转移的方法。作为我们的次要总体目标，我们发现了共同的 具有头部/颈部SCC和肺SCC的解剖学与ESCC之间的生物学行为原理 以及肺腺癌（LAC）的EAC。对于我们的第三个总体目标，我们试图翻译 我们的新型3D器官培养/3D器官和小鼠模型，人体组织中的发现和临床前的发现 对患者的临床试验的治疗研究。我们的集成和凝聚力3个项目和3个核心设施， 在我们机构的明确支持下，内部和外部咨询委员会的严格审查， 对食管癌和相关癌症的领域产生了重大影响。每个项目和 核心具有特定的目标和研究策略，这些策略通过智力概念，模型交织在一起 通过单个赠款无法实现的系统/试剂和实验方法。 该P01竞争更新中的关键概念和方法与细胞周期蛋白D1/CDK4和细胞周期蛋白E有关 通过新的治疗方法进行CDK4/6抑制作用和免疫微环境的放松管制， CDK2抑制（细胞周期蛋白E激酶伴侣）和谷氨酰胺抑制（由于面部添加谷氨酰胺 Cyclin D1过表达）；突变p53及其在内吞回收，肿瘤侵袭和肿瘤中的作用 转移;和肿瘤微环境中的细胞因子具有治疗性靶向。我们的 协同作用使我们在可见出版物，会议上的演讲中提高了高产性， 通过扩大现场调查人员并在工作队的领导地位来影响该领域 我们将更多地增强。总体而言，我们的集成和严格的项目由 创新的核心将塑造食道癌的景观。