Mechanisms of Esophageal Carcinogenesis

项目概要-总体 食道癌在世界范围内很常见。有两种主要的亚型：食管鳞状细胞 癌（ESCC）和食管腺癌（EAC）。前驱病变包括食管鳞状上皮 异型增生和食管肠上皮化生（=Barrett食管）。分子 ESCC和EAC的发病机制涉及基因组畸变（例如，细胞周期蛋白D1、细胞周期蛋白E、表皮生长 因子受体或EGFR），遗传突变或缺失（例如TP 53，p120连环蛋白），表观遗传改变， 转录组紊乱和与环境/生活方式变量的相互作用。作为我们的主要 总体目标，我们已经取得了重大进展，在这个综合方案项目（P01）， ESCC和EAC分子发病机制的鉴定和表征 与肿瘤细胞中的基因组和遗传“潜水员”有关， 以及肿瘤转移的途径。作为我们的第二个首要目标，我们正在发现共同的 头颈部鳞状细胞癌与肺鳞状细胞癌生物学行为的关系 以及EAC与肺腺癌（LAC）。我们的第三个总体目标是， 我们的新型3D器官型培养/3D类器官和小鼠模型，在人体组织中的发现，以及临床前 从治疗研究到患者的临床试验。我们整合和凝聚的3个项目和3个核心设施， 我们得到各院校的明确支持，内部和外部咨询委员会的严格审查， 对食管癌及相关癌症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，这些目标和策略通过知识概念、模型 系统/试剂和实验方法，这是不可能通过个人赠款。 P01竞争性更新的基本概念和方法涉及细胞周期蛋白D1/CDK 4和细胞周期蛋白E 用新的治疗方法去调节CDK 4/6抑制和免疫微环境， CDK 2抑制（细胞周期蛋白E激酶伴侣）和谷氨酰胺酶抑制（由于在面部添加谷氨酰胺 突变型p53及其在内吞循环、肿瘤侵袭和肿瘤发生中的作用 转移;以及具有治疗靶向的肿瘤微环境中的RANTES细胞因子。我们 协同作用使我们在可见的出版物，会议上的演讲， 通过增加外地调查员和领导工作队来影响外地， 我们将进一步扩大。总的来说，我们的综合和严格的项目，支持由 创新的核心，将塑造食道癌的景观。

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.