PROJECT SUMMARY 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, finding 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.