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 journalArticle

5 Citations (Scopus)

Abstract

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
JournalCMGH
Volume7
Issue number1
DOIs
Publication statusPublished - Jan 1 2019
Externally publishedYes

Fingerprint

Organoids
Neoplasms
Fluorouracil
Therapeutics
Precision Medicine
Esophageal Squamous Cell Carcinoma
Autophagy
Cell- and Tissue-Based Therapy
Mucous Membrane

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Kijima, T., Nakagawa, H., Shimonosono, M., Chandramouleeswaran, P. M., Hara, T., Sahu, V., ... Natsugoe, S. (2019). Three-Dimensional Organoids Reveal Therapy Resistance of Esophageal and Oropharyngeal Squamous Cell Carcinoma Cells. CMGH, 7(1), 73-91. https://doi.org/10.1016/j.jcmgh.2018.09.003

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

In: CMGH, Vol. 7, No. 1, 01.01.2019, p. 73-91.

Research output: Contribution to journalArticle

Kijima, T, Nakagawa, H, Shimonosono, M, Chandramouleeswaran, PM, Hara, T, Sahu, V, Kasagi, Y, Kikuchi, O, Tanaka, K, Giroux, V, Muir, AB, Whelan, KA, Ohashi, S, Naganuma, S, Klein-Szanto, AJ, Shinden, Y, Sasaki, K, Omoto, I, Kita, Y, Muto, M, Bass, AJ, Diehl, JA, Ginsberg, GG, Doki, Y, Mori, M, Uchikado, Y, Arigami, T, Avadhani, NG, Basu, D, Rustgi, AK & Natsugoe, S 2019, 'Three-Dimensional Organoids Reveal Therapy Resistance of Esophageal and Oropharyngeal Squamous Cell Carcinoma Cells', CMGH, vol. 7, no. 1, pp. 73-91. https://doi.org/10.1016/j.jcmgh.2018.09.003
Kijima T, Nakagawa H, Shimonosono M, Chandramouleeswaran PM, Hara T, Sahu V et al. Three-Dimensional Organoids Reveal Therapy Resistance of Esophageal and Oropharyngeal Squamous Cell Carcinoma Cells. CMGH. 2019 Jan 1;7(1):73-91. https://doi.org/10.1016/j.jcmgh.2018.09.003
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. / Three-Dimensional Organoids Reveal Therapy Resistance of Esophageal and Oropharyngeal Squamous Cell Carcinoma Cells. In: CMGH. 2019 ; Vol. 7, No. 1. pp. 73-91.
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T1 - Three-Dimensional Organoids Reveal Therapy Resistance of Esophageal and Oropharyngeal Squamous Cell Carcinoma Cells

AU - Kijima, Takashi

AU - Nakagawa, Hiroshi

AU - Shimonosono, Masataka

AU - Chandramouleeswaran, Prasanna M.

AU - Hara, Takeo

AU - Sahu, Varun

AU - Kasagi, Yuta

AU - Kikuchi, Osamu

AU - Tanaka, Koji

AU - Giroux, Veronique

AU - Muir, Amanda B.

AU - Whelan, Kelly A.

AU - Ohashi, Shinya

AU - Naganuma, Seiji

AU - Klein-Szanto, Andres J.

AU - Shinden, Yoshiaki

AU - Sasaki, Ken

AU - Omoto, Itaru

AU - Kita, Yoshiaki

AU - Muto, Manabu

AU - Bass, Adam J.

AU - Diehl, J. Alan

AU - Ginsberg, Gregory G.

AU - Doki, Yuichiro

AU - Mori, Masaki

AU - Uchikado, Yasuto

AU - Arigami, Takaaki

AU - Avadhani, Narayan G.

AU - Basu, Devraj

AU - Rustgi, Anil K.

AU - Natsugoe, Shoji

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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