Cellular and Molecular Gastroenterology and Hepatology (Jan 2019)
Three-Dimensional Organoids Reveal Therapy Resistance of Esophageal and Oropharyngeal Squamous Cell Carcinoma CellsSummary
- 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 Muto,
- Adam 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
Affiliations
- Takashi Kijima
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Hiroshi Nakagawa
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania; Correspondence Address correspondence to: Hiroshi Nakagawa, MD, PhD, Cell Culture and iPS Core, Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 956 Biomedical Research Building, 421 Curie Boulevard, Philadelphia, PA 19104-6160. fax: (215) 573-2024.
- Masataka Shimonosono
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania
- Prasanna M. Chandramouleeswaran
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania
- Takeo Hara
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
- Varun Sahu
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
- Yuta Kasagi
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Osamu Kikuchi
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Koji Tanaka
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania; Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
- Veronique Giroux
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania
- Amanda B. Muir
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Kelly A. Whelan
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania; Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
- Shinya Ohashi
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Seiji Naganuma
- Department of Pathology, Kochi University School of Medicine, Nankoku, Japan
- Andres J. Klein-Szanto
- Histopathology Facility and Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
- Yoshiaki Shinden
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Ken Sasaki
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Itaru Omoto
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Yoshiaki Kita
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Manabu Muto
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Adam J. Bass
- Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts
- J. Alan Diehl
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
- Gregory G. Ginsberg
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania
- Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
- Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
- Yasuto Uchikado
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Takaaki Arigami
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Narayan G. Avadhani
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Devraj Basu
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
- Anil K. Rustgi
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania; Anil K. Rustgi, MD, Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 951 Biomedical Research Building, 421 Curie Boulevard, Philadelphia, PA 19104-4863. fax: (215) 573-5412.
- Shoji Natsugoe
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; Shoji Natsugoe, MD, PhD, Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. fax: (81) (99) 265-7426.
- Journal volume & issue
-
Vol. 7,
no. 1
pp. 73 – 91
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. Keywords: 3D Organoids, Autophagy, CD44, 5-Fluorouracil
