Three-Dimensional Organoids Reveal Therapy Resistance of Esophageal and Oropharyngeal Squamous Cell Carcinoma Cells

Takashi Kijima, Hiroshi Nakagawa, Masataka Shimonosono, Prasanna M. Chandramouleeswaran, Takeo Hara, Varun Sahu, Yuta Kasagi, Osamu Kikuchi, Koji Tanaka, Veronique Giroux, Amanda B. Muir, Kelly A. Whelan, Shinya Ohashi, Seiji Naganuma, Andres J. Klein-Szanto, Yoshiaki Shinden, Ken Sasaki, Itaru Omoto, Yoshiaki Kita, Manabu MutoAdam J. Bass, J. Alan Diehl, Gregory G. Ginsberg, Yuichiro Doki, Masaki Mori, Yasuto Uchikado, Takaaki Arigami, Narayan G. Avadhani, Devraj Basu, Anil K. Rustgi, Shoji Natsugoe

Research output: Contribution to journalArticlepeer-review

83 Citations (Scopus)


Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)73-91
Number of pages19
Issue number1
Publication statusPublished - 2019

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology


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