TY - JOUR
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
N1 - Funding Information:
Funding This study was supported by the Grant-in-Aid for challenging Exploratory Research , Grant in Aid for Scientific Research B and Grant in Aid for Scientific Research C from the Ministry of Education, Culture, Sports, Science and Technology of Japan ( 17H04285 to SN; and 15K10108 to YK). This study was also supported by the following NIH Grants: P01CA098101 (HN, KT, KAW, VG, AJK, AB, JAD, AKR), U54CA163004 (HN, GGG, AKR), R01DK114436 (HN), R01AA026297 (HN), R01AA022986 (NGA), P30ES013508 University of Pennsylvania Center of Excellence in Environmental Toxicology (HN and AKR), K01DK103953 (KAW), F32CA174176 (KAW), T32DK007066 (KAW), K08DK106444 (ABM), the American Cancer Society RP-10-033-01-CCE (AKR), NIH/NIDDK P30DK050306 Center of Molecular Studies in Digestive and Liver Diseases, The Molecular Pathology and Imaging, Molecular Biology/Gene Expression, Cell Culture/iPS and Mouse Core Facilities. KT is a recipient of the Japan Society for the Promotion of Science Postdoctoral Fellowship. VG is a recipient of the Fonds de Recherche du Québec – Santé Postdoctoral Fellowship (P-Giroux-27692 and P-Giroux-31601).
Publisher Copyright:
© 2018 The Authors
PY - 2019
Y1 - 2019
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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U2 - 10.1016/j.jcmgh.2018.09.003
DO - 10.1016/j.jcmgh.2018.09.003
M3 - Article
C2 - 30510992
AN - SCOPUS:85056946814
SN - 2352-345X
VL - 7
SP - 73
EP - 91
JO - CMGH
JF - CMGH
IS - 1
ER -
