Patient-derived tumor organoid cultures identify a chemo-resistant sub-population in esophageal squamous cell carcinoma

Abstract

Background: Patient-derived xenograft has been a gold standard for cancer modeling. However, low establishment efficiency and high maintenance cost have hindered the development in the field. In recent years, patient-derived tumor organoid culture has been developed as an efficient and economic model to mimic and recapitulate the original tumor tissue, in contrast to conventional cancer cell lines and patient-derived xenografts (Drost & Clevers, 2018). Due to the limited availability of current esophageal squamous cell carcinoma (ESCC) models, we aimed to establish a panel of ESCC patient-derived organoid (PDO) long-term cultures for ESCC study. Results: In the current project, we have established and biobanked a panel of ESCC PDO cultures in vitro from Chinese ESCC treatment-naïve patients undergoing an endoscopic examination or upfront surgery, or patients undergoing neoadjuvant chemoradiotherapy (CRT) followed by surgery in Hong Kong. We also established and maintained PDO-derived xenograft (PDOX) in immunocompromised mice. Immunohistochemical examination confirmed the squamous origin of the established PDOs and PDOXs. Genomic profiling showed consistent mutational landscapes of the established PDO, as compared to ESCC patient profiles. Transcriptomic profiling suggests organoid culture resembles patient tissue samples better than the cell line model in terms of global gene expression patterns. Notably, PDOs from CRT-treated patients show enhanced re-growth after recovery from cisplatin treatment, indicating a candidate cancer stem cell (CSC) sub-population enriched by neoadjuvant CRT. This sub-population can be further enriched in vitro by serial cisplatin treatment and recovery cycles. Conclusions: ESCC PDOs can be efficiently established from highly limited patient tissue samples and maintained long-term in vitro and can be feasibly integrated with mouse model. It preserves the original cell hierarchy and indicates existence of candidate CSC sub-population, which may be targeted therapeutically in future. Reference: Drost J, Clevers H. Organoids in cancer research. Nat Rev Cancer. 2018 Jul; 18(7).