modeling-oral-esophageal-squamous-cell-carcinoma-in-3d-organoids

Modeling Oral-Esophageal Squamous Cell Carcinoma in 3D Organoids

Esophageal squamous cell carcinoma (ESCC) is prevalent worldwide, accounting for 90% of all esophageal cancer cases each year, and is the deadliest of all ...

Columbia University

Columbia College

Three-dimensional (3D) organoids are a novel tool to model epithelial cell biology and human diseases of the esophagus. 3D organoid culture systems have been utilized to investigate the pathobiology of esophageal cancer, including both squamous cell carcinoma and adenocarcinoma. Additional organoid-based approaches for study of esophageal development and benign esophageal diseases have provided key insights into esophageal keratinocyte differentiation and mucosal regeneration. These investigations have implications for the identification of esophageal cancer stem cells, as well as the potential to halt malignant progression through induction of differentiation pathways. Patient-derived organoids (PDOs) from human tissue samples allow for unique and faithful in vitro modeling of esophageal cancers, and provide an exciting platform for investigation into personalized medicine and targeted treatment approaches, as well as new models for understanding therapy resistance and recurrent disease. Future directions include high-throughput genomic screening using PDOs, and study of tumor-microenvironmental interactions through co-culture with immune and stromal cells and novel extracellular matrix complexes.

Understanding the cellular origin and progression of esophageal cancer using esophageal organoids.

Alcohol (ethanol) consumption is a major risk factor for head and neck and esophageal squamous cell carcinomas (SCCs). However, how ethanol (EtOH) affects SCC homeostasis is incompletely understood.

Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy.

The microbiome is an emerging key co-factor in the development of esophageal cancer, the sixth leading cause of cancer death worldwide. However, there is a paucity of data delineating how the microbiome contributes to the pathobiology of the two histological subtypes of esophageal cancer: esophageal squamous cell carcinoma and esophageal adenocarcinoma. This critical knowledge gap is partially due to inadequate modeling of host-microbiome interactions in the etiology of esophageal cancers. Recent advances have enabled progress in this field. Three dimensional (3D) organoids faithfully recapitulate the structure and function of the normal, preneoplastic, and neoplastic epithelia of the esophagus ex vivo and serve as a platform translatable for applications in precision medicine. Elsewhere in the gastrointestinal (GI) tract, the co-culture of 3D organoids with the bacterial microbiome has fostered insight into the pathogenic role of the microbiome in other GI cancers. Herein, we will summarize our current understanding of the relationship between the microbiome and esophageal cancer, discuss 3D organoid models of esophageal homeostasis, review analogous models of host-microbiome interactions in other GI cancers, and advocate for the application of these models to esophageal cancers. Together, we present a promising, novel approach with the potential to ameliorate the burden of esophageal cancer-related morbidity and mortality via improved prevention and therapeutic interventions.

3D Organoids: An Untapped Platform for Studying Host-Microbiome Interactions in Esophageal Cancers.

Eosinophilic esophagitis (EoE) is a chronic allergic disease associated with type 2 inflammation and epithelial barrier dysfunction. The etiology is unknown, however, genetic heritability studies suggest environmental factors play a key role in pathogenesis. Detergents, such as sodium dodecyl sulfate (SDS), are common ingredients in household products such as dish soap and toothpaste. We hypothesized detergent exposure decreases epithelial barrier function and induces esophageal inflammation.

Detergent exposure induces epithelial barrier dysfunction and eosinophilic inflammation in the esophagus.

Heterogeneous Nuclear Ribonucleoprotein K (hnRNPK) is a multifunctional RNA binding protein (RBP) localized in the nucleus and the cytoplasm. Abnormal cytoplasmic enrichment observed in solid tumors often correlates with poor clinical outcome. The mechanism of cytoplasmic redistribution and ensuing functional role of cytoplasmic hnRNPK remain unclear. Here we demonstrate that the SCF E3 ubiquitin ligase restricts the pro-oncogenic activity of hnRNPK via K63 linked polyubiquitylation, thus limiting its ability to bind target mRNA. We identify SCF-hnRNPK responsive mRNAs whose products regulate cellular processes including proliferation, migration, and invasion. Loss of SCF leads to enhanced cell invasion, migration, and tumor metastasis. C-Myc was identified as one target of SCF-hnRNPK. Fbxo4 loss triggers hnRNPK-dependent increase in c-Myc translation, thereby contributing to tumorigenesis. Increased c-Myc positions SCF-hnRNPK dysregulated cancers for potential therapeutic interventions that target c-Myc-dependence. This work demonstrates an essential role for limiting cytoplasmic hnRNPK function in order to maintain translational and cellular homeostasis.

Article	Year
Understanding the cellular origin and progression of esophageal cancer using esophageal organoids. Cancer letters\| PubMed ID: 33838281	2021
Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy. Biomolecules\| PubMed ID: 34680112	2021
3D Organoids: An Untapped Platform for Studying Host-Microbiome Interactions in Esophageal Cancers. Microorganisms\| PubMed ID: 34835308	2021
Detergent exposure induces epithelial barrier dysfunction and eosinophilic inflammation in the esophagus. Allergy\| PubMed ID: 35899466	2022
Tumor suppressor mediated ubiquitylation of hnRNPK is a barrier to oncogenic translation. Nature communications\| PubMed ID: 36329064	2022

Samuel Flashner

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