Title: Three-Dimensional Organoids Reveal Therapy Resistance of Esophageal and Oropharyngeal Squamous Cell Carcinoma Cells.
Authors: Kijima, Takashi; Nakagawa, Hiroshi; Shimonosono, Masataka; Chandramouleeswaran, Prasanna M; Hara, Takeo; Sahu, Varun; Kasagi, Yuta; Kikuchi, Osamu; Tanaka, Koji; Giroux, Veronique; Muir, Amanda B; Whelan, Kelly A; Ohashi, Shinya; Naganuma, Seiji; Klein-Szanto, Andres J; Shinden, Yoshiaki; Sasaki, Ken; Omoto, Itaru; Kita, Yoshiaki; Muto, Manabu; Bass, Adam J; Diehl, J Alan; Ginsberg, Gregory G; Doki, Yuichiro; Mori, Masaki; Uchikado, Yasuto; Arigami, Takaaki; Avadhani, Narayan G; Basu, Devraj; Rustgi, Anil K; Natsugoe, Shoji
Published In Cell Mol Gastroenterol Hepatol, (2019)
Abstract: Oropharyngeal and esophageal squamous cell carcinomas, especially the latter, are a lethal disease, featuring intratumoral cancer cell heterogeneity and therapy resistance. To facilitate cancer therapy in personalized medicine, three-dimensional (3D) organoids may be useful for functional characterization of cancer cells ex vivo. We investigated the feasibility and the utility of patient-derived 3D organoids of esophageal and oropharyngeal squamous cell carcinomas.We generated 3D organoids from paired biopsies representing tumors and adjacent normal mucosa from therapy-naïve patients and cell lines. We evaluated growth and structures of 3D organoids treated with 5-fluorouracil ex vivo.Tumor-derived 3D organoids were grown successfully from 15 out of 21 patients (71.4%) and passaged with recapitulation of the histopathology of the original tumors. Successful formation of tumor-derived 3D organoids was associated significantly with poor response to presurgical neoadjuvant chemotherapy or chemoradiation therapy in informative patients (P = 0.0357, progressive and stable diseases, n = 10 vs. partial response, n = 6). The 3D organoid formation capability and 5-fluorouracil resistance were accounted for by cancer cells with high CD44 expression and autophagy, respectively. Such cancer cells were found to be enriched in patient-derived 3D organoids surviving 5-fluorouracil treatment.The single cell-based 3D organoid system may serve as a highly efficient platform to explore cancer therapeutics and therapy resistance mechanisms in conjunction with morphological and functional assays with implications for translation in personalized medicine.
PubMed ID: 30510992
MeSH Terms: Animals; Autophagy/drug effects; Biopsy; Carcinoma, Squamous Cell/pathology*; Carcinoma, Squamous Cell/therapy; Cell Line, Tumor; Chemoradiotherapy; Drug Resistance, Neoplasm*; Endoscopy; Esophageal Neoplasms/pathology*; Fluorouracil/pharmacology; Fluorouracil/therapeutic use; Humans; Hyaluronan Receptors/metabolism; Mice; Organoids/pathology*; Oropharyngeal Neoplasms/pathology*; Oropharyngeal Neoplasms/therapy