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

Abstract

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.

Keywords: 3D organoids; Barrett's esophagus; Esophageal adenocarcinoma; Esophageal squamous cell carcinoma; Esophageal stem cells.

Figure 1.. Pathway of Organoid Generation for Scientific or Preclinical Studies.

Organoids can be generated from patient biopsies or animal models of esophageal diseases, including normal or treated esophagus, primary esophageal cancer tissue, or metastases to lung or other organs. Esophageal epithelium or tumor tissues are dissociated into single cells and seeded in Matrigel. Organoids can be cultured in the presence of specific chemical treatments or subject to genetic manipulation in vitro, followed by cell-based analyses and in vitro or in vivo modeling of disease through culture-based or xenograft models.

Figure 2.. Patient-Derived Organoids to Model Esophageal Cancer.

Hematoxylin and Eosin stained sections of fixed 3D organoids derived from the non-transformed human esophageal epithelial EPC2-hTERT cell line, and from ESCC, BE, and EAC PDO lines derived from human patient biopsies.