EPHB2-Dependent Signaling: A New Molecular Paradigm in Barrett's Neoplasia

EPHB2 依赖性信号传导：巴雷特瘤形成的新分子范式

• 批准号: 10713941
• 负责人: Andrew Edward Blum
• 金额: $ 40.81万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713941
• 关键词: 3-Dimensional; Acceleration; Animal Model; Barrett Esophagus; Barrett' s carcinogenesis; Barrett' s neoplasia; Bile Acids; Binding; Binding Proteins; Biological; Biological Markers; Biopsy; Cell Line; Cell Lineage; Cells; Chemopreventive Agent; Complex; Coupled; Development; Disease; Disease Progression; Distal; Dysplasia; EPHB2 gene; Ephrin-B2; Epithelium; Esophageal Adenocarcinoma; Esophageal Squamous Cell; Esophageal injury; Esophageal mucous membrane; Esophagus; Etiology; Exposure to; Family suidae; Gastroenterology; Genetic Transcription; Gland; Goals; Human; In Situ; In Vitro; Inflammation; Inflammatory; Inherited; Injury; Interleukin-1 beta; Intestines; Lesion; Link; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metaplasia; Modeling; Molecular; Mucous Membrane; Mus; NF-kappa B; Neoplasms; Organoids; Pathogenesis; Pathologic; Pathway Analysis; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphotransferases; Predisposition; Receptor Protein-Tyrosine Kinases; Reflux; Regulation; Risk; Risk Factors; Rodent Model; Role; Signal Transduction; Source; Submucosa; Testing; Therapeutic; Time; Tissues; Transcriptional Regulation; Transitional Cell; United States; c-myc Genes; cancer prevention; carcinogenesis; clinical implementation; design; evidence base; genome-wide; in vivo; injury and repair; molecular shape; mouse model; novel; phosphoproteomics; preclinical study; precursor cell; progenitor; programs; promoter; single-cell RNA sequencing; stem cells; synergism; transcription factor; transcriptome sequencing; transcriptomics; tumor growth; ubiquitin-protein ligase; wound healing

PROJECT SUMMARY/ABSTRACT The etiology of Barrett's esophagus (BE), a molecularly complex disorder of the distal esophagus, remains elusive. Patients with BE are at an increased risk of developing esophageal adenocarcinoma (EAC), a lethal, increasingly prevalent, and the most common esophageal malignancy in the U.S. Our long-term objective is to identify the causative mechanisms underlying the onset and malignant progression of BE, and to develop evidence-based biomarkers and chemopreventive/therapeutic strategies for subsequent clinical implementation. Project 3 of this program is based on our recent discovery of EphB2 Receptor Tyrosine Kinase as a novel promoter of Barrett's neoplasia. RNA sequencing coupled with pathway modeling in treatment-naïve patient biopsies showed significant hyperactivation of EphB2 signaling in the vast majority (>90%) of BE and EAC lesions. Phenotypic assessments in vitro and in vivo demonstrated EphB2 signaling to be essential for the viability of EAC and dysplastic/BE cells. Subsequent mechanistic studies identified c-MYC as a novel target of EphB2 signaling, while single-cell RNA sequencing of esophageal progenitor cells further confirmed a strong association of EphB2 activation with columnar/BE-like cell lineage. Collectively, our study implicates EphB2 signaling for the first time in BE-EAC pathogenesis, and further reveals a novel link between EphB2 and MYC in any disease context. Expanding on these provocative findings, we now propose to fully characterize the biologic role of EphB2 in Barrett's neoplasia as follows: In Aim 1, we will determine whether EphB2 activation is a consequence of, or a pre-requisite for, columnar/BE metaplasia development. We will test whether activation of EphB2 signaling in putative BE-progenitor cells promote columnar/BE-like transformative state. In Aim 2, we will determine the pathologic consequences of EphB2 activation in vivo in the esophagus, using a constitutively- active EphB2 kinase (Ephb2F613D) mouse model that we recently developed. We will specifically test if EphB2 activation induces BE-like metaplasia and dysplasia/cancer in the esophagus; either spontaneously, or upon exposure to reflux injury, and/or in the setting of esophageal inflammation. We will further characterize the key molecular programs disrupted by EphB2 activation in the esophagus. In Aim 3, we will determine the downstream and upstream regulatory cascades of EphB2 signaling. Collectively, our proposed studies will delineate the role of EphB2 signaling for the first time, uncovering novel driver mechanisms of BE-EAC pathogenesis.

项目总结/文摘