Journal
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Volume 7, Issue 1, Pages 73-91Publisher
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2018.09.003
Keywords
3D Organoids; Autophagy; CD44; 5-Fluorouracil
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [17H04285, 15K10108]
- NIH [P01CA098101, U54CA163004, R01DK114436, R01AA026297, R01AA022986]
- University of Pennsylvania Center of Excellence in Environmental Toxicology [K01DK103953, F32CA174176, T32DK007066, K08DK106444, P30ES013508]
- American Cancer Society [RP-10-033-01-CCE]
- NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases [P30DK050306]
- Japan Society for the Promotion of Science Postdoctoral Fellowship
- Fonds de Recherche du Quebec - Sante Postdoctoral Fellowship [P-Giroux-27692, P-Giroux-31601]
- Molecular Pathology and Imaging, Molecular Biology/Gene Expression, Cell Culture/iPS and Mouse Core Facilities
- NATIONAL CANCER INSTITUTE [U54CA163004, P01CA098101] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [T32DK007066, K08DK106444, R01DK114436, P30DK050306, K01DK103953] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [P30ES013508] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R01AA022986, R01AA026297] Funding Source: NIH RePORTER
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We have established 3 dimensional organoids from patients with esophageal and oropharyngeal squamous cell carcinomas. We show that 3-dimensional organoids reveal resistance mechanisms and provide a robust platform to predict therapy response in the setting of personalized medicine. 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-naive 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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