Mechanisms of Esophageal Carcinogenesis

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.

Overarching Objectives

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.

Project Structure

Our integrated and cohesive three projects and three 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.

Public Health Relevance Statement

Esophageal cancer has two major subtypes: esophageal squamous cell cancer and esophageal adenocarcinoma. Challenges remain with the dismal prognosis for each. We are employing integrated efforts involving genomics, genetics, 3D culture and mouse models, human tissues and preclinical trials to improve our mechanistic understanding and innovations in translational therapeutics so as to improve prognosis and survival.

Projects

Transformed Esophageal Epithelial Cells and the Tumor Microenvironment

A study of mutant p53 as well as cancer associated fibroblasts and their roles in the tumor microenvironment to foster stromal invasion and metastasis with opportunities for therapeutic intervention.

Protein Ubiquitylation in Esophageal Cancer

Threshold levels of cyclin D1/CDK4 kinase and other proteins are maintained by E3 ligases. However, overexpression of these proteins results in cellular vulnerabilities that can be rationally targeted in esophageal cancer.

Genome-Guided Therapeutic Vulnerabilities in Esophageal Cancer

Beyond their roles in promoting cell cycle and proliferation, the amplification of Cyclin D1 and Cyclin E1 have consequences on tumor microenvironment and genomic stability. This project investigates the optimal therapeutic implications of the  cyclin D1 and E1 proteins.