Establishment of Patient-Derived Organoids and Drug Screening for Biliary Tract Carcinoma

Biliary tract carcinomas (BTCs) are among the most aggressive malignancies and have a poor prognosis. Here, we successfully established organoid lines derived from intrahepatic cholangiocarcinoma, gallbladder cancer, and neuroendocrine carcinoma of the ampulla of Vater. These organoids derived from...

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Published in	Cell reports (Cambridge) Vol. 27; no. 4; pp. 1265 - 1276.e4
Main Authors	Saito, Yoshimasa, Muramatsu, Toshihide, Kanai, Yae, Ojima, Hidenori, Sukeda, Aoi, Hiraoka, Nobuyoshi, Arai, Eri, Sugiyama, Yuko, Matsuzaki, Juntaro, Uchida, Ryoei, Yoshikawa, Nao, Furukawa, Ryo, Saito, Hidetsugu
Format	Journal Article
Language	English
Published	United States Elsevier Inc 23.04.2019
Subjects	antifungal drug biliary tract carcinoma drug screening gallbladder cancer intrahepatic cholangiocarcinoma neuroendocrine carcinoma of the ampulla of Vater organoid culture gallbladder cancer neuroendocrine carcinoma of the ampulla of Vater drug screening organoid culture biliary tract carcinoma antifungal drug intrahepatic cholangiocarcinoma
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Abstract	Biliary tract carcinomas (BTCs) are among the most aggressive malignancies and have a poor prognosis. Here, we successfully established organoid lines derived from intrahepatic cholangiocarcinoma, gallbladder cancer, and neuroendocrine carcinoma of the ampulla of Vater. These organoids derived from BTCs were cultured stably for >1 year and closely recapitulated the histopathology, gene expression, and genetic alterations evident in the primary tumors. Gene expression profiling of the organoids revealed that SOX2 could be a potential prognostic biomarker for patients with BTC. We screened a compound library consisting of drugs used clinically for their ability to suppress organoids derived from BTCs and found that the antifungal drugs amorolfine and fenticonazole significantly suppressed the growth of organoids derived from BTCs with minimal toxicity to normal biliary epithelial cells. Patient-derived organoids may be a powerful research tool for the clarification of molecular pathogenesis and the discovery of biomarkers and therapeutic drugs for refractory cancers. [Display omitted] •Establishment of organoids derived from biliary tract carcinoma (BTC) patients•Biological similarity between the primary BTC tissues and established organoids•Identification of SOX2, KLK6, and CPB2 as prognostic biomarkers for BTC patients•Drug screening identified antifungal drugs as potential therapeutic agents for BTC Saito et al. were successful in establishing and long-term in vitro culturing of organoids derived from patients with intrahepatic cholangiocarcinoma, gallbladder cancer, and neuroendocrine carcinoma of the ampulla of Vater. Patient-derived organoids can be a powerful preclinical model to identify prognostic biomarkers and therapeutic agents for biliary tract carcinoma.
AbstractList	Biliary tract carcinomas (BTCs) are among the most aggressive malignancies and have a poor prognosis. Here, we successfully established organoid lines derived from intrahepatic cholangiocarcinoma, gallbladder cancer, and neuroendocrine carcinoma of the ampulla of Vater. These organoids derived from BTCs were cultured stably for >1 year and closely recapitulated the histopathology, gene expression, and genetic alterations evident in the primary tumors. Gene expression profiling of the organoids revealed that SOX2 could be a potential prognostic biomarker for patients with BTC. We screened a compound library consisting of drugs used clinically for their ability to suppress organoids derived from BTCs and found that the antifungal drugs amorolfine and fenticonazole significantly suppressed the growth of organoids derived from BTCs with minimal toxicity to normal biliary epithelial cells. Patient-derived organoids may be a powerful research tool for the clarification of molecular pathogenesis and the discovery of biomarkers and therapeutic drugs for refractory cancers. [Display omitted] •Establishment of organoids derived from biliary tract carcinoma (BTC) patients•Biological similarity between the primary BTC tissues and established organoids•Identification of SOX2, KLK6, and CPB2 as prognostic biomarkers for BTC patients•Drug screening identified antifungal drugs as potential therapeutic agents for BTC Saito et al. were successful in establishing and long-term in vitro culturing of organoids derived from patients with intrahepatic cholangiocarcinoma, gallbladder cancer, and neuroendocrine carcinoma of the ampulla of Vater. Patient-derived organoids can be a powerful preclinical model to identify prognostic biomarkers and therapeutic agents for biliary tract carcinoma. Biliary tract carcinomas (BTCs) are among the most aggressive malignancies and have a poor prognosis. Here, we successfully established organoid lines derived from intrahepatic cholangiocarcinoma, gallbladder cancer, and neuroendocrine carcinoma of the ampulla of Vater. These organoids derived from BTCs were cultured stably for >1 year and closely recapitulated the histopathology, gene expression, and genetic alterations evident in the primary tumors. Gene expression profiling of the organoids revealed that SOX2 could be a potential prognostic biomarker for patients with BTC. We screened a compound library consisting of drugs used clinically for their ability to suppress organoids derived from BTCs and found that the antifungal drugs amorolfine and fenticonazole significantly suppressed the growth of organoids derived from BTCs with minimal toxicity to normal biliary epithelial cells. Patient-derived organoids may be a powerful research tool for the clarification of molecular pathogenesis and the discovery of biomarkers and therapeutic drugs for refractory cancers.Biliary tract carcinomas (BTCs) are among the most aggressive malignancies and have a poor prognosis. Here, we successfully established organoid lines derived from intrahepatic cholangiocarcinoma, gallbladder cancer, and neuroendocrine carcinoma of the ampulla of Vater. These organoids derived from BTCs were cultured stably for >1 year and closely recapitulated the histopathology, gene expression, and genetic alterations evident in the primary tumors. Gene expression profiling of the organoids revealed that SOX2 could be a potential prognostic biomarker for patients with BTC. We screened a compound library consisting of drugs used clinically for their ability to suppress organoids derived from BTCs and found that the antifungal drugs amorolfine and fenticonazole significantly suppressed the growth of organoids derived from BTCs with minimal toxicity to normal biliary epithelial cells. Patient-derived organoids may be a powerful research tool for the clarification of molecular pathogenesis and the discovery of biomarkers and therapeutic drugs for refractory cancers. Biliary tract carcinomas (BTCs) are among the most aggressive malignancies and have a poor prognosis. Here, we successfully established organoid lines derived from intrahepatic cholangiocarcinoma, gallbladder cancer, and neuroendocrine carcinoma of the ampulla of Vater. These organoids derived from BTCs were cultured stably for >1 year and closely recapitulated the histopathology, gene expression, and genetic alterations evident in the primary tumors. Gene expression profiling of the organoids revealed that SOX2 could be a potential prognostic biomarker for patients with BTC. We screened a compound library consisting of drugs used clinically for their ability to suppress organoids derived from BTCs and found that the antifungal drugs amorolfine and fenticonazole significantly suppressed the growth of organoids derived from BTCs with minimal toxicity to normal biliary epithelial cells. Patient-derived organoids may be a powerful research tool for the clarification of molecular pathogenesis and the discovery of biomarkers and therapeutic drugs for refractory cancers.
Author	Sugiyama, Yuko Saito, Yoshimasa Furukawa, Ryo Arai, Eri Muramatsu, Toshihide Hiraoka, Nobuyoshi Matsuzaki, Juntaro Kanai, Yae Sukeda, Aoi Ojima, Hidenori Saito, Hidetsugu Uchida, Ryoei Yoshikawa, Nao
Author_xml	– sequence: 1 givenname: Yoshimasa surname: Saito fullname: Saito, Yoshimasa email: saito-ys@pha.keio.ac.jp organization: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan – sequence: 2 givenname: Toshihide surname: Muramatsu fullname: Muramatsu, Toshihide organization: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan – sequence: 3 givenname: Yae surname: Kanai fullname: Kanai, Yae organization: Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan – sequence: 4 givenname: Hidenori surname: Ojima fullname: Ojima, Hidenori organization: Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan – sequence: 5 givenname: Aoi surname: Sukeda fullname: Sukeda, Aoi organization: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan – sequence: 6 givenname: Nobuyoshi surname: Hiraoka fullname: Hiraoka, Nobuyoshi organization: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan – sequence: 7 givenname: Eri surname: Arai fullname: Arai, Eri organization: Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan – sequence: 8 givenname: Yuko surname: Sugiyama fullname: Sugiyama, Yuko organization: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan – sequence: 9 givenname: Juntaro surname: Matsuzaki fullname: Matsuzaki, Juntaro organization: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan – sequence: 10 givenname: Ryoei surname: Uchida fullname: Uchida, Ryoei organization: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan – sequence: 11 givenname: Nao surname: Yoshikawa fullname: Yoshikawa, Nao organization: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan – sequence: 12 givenname: Ryo surname: Furukawa fullname: Furukawa, Ryo organization: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan – sequence: 13 givenname: Hidetsugu surname: Saito fullname: Saito, Hidetsugu organization: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/31018139$$D View this record in MEDLINE/PubMed
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Keywords	gallbladder cancer neuroendocrine carcinoma of the ampulla of Vater drug screening organoid culture biliary tract carcinoma antifungal drug intrahepatic cholangiocarcinoma
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Snippet	Biliary tract carcinomas (BTCs) are among the most aggressive malignancies and have a poor prognosis. Here, we successfully established organoid lines derived...
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SubjectTerms	antifungal drug biliary tract carcinoma drug screening gallbladder cancer intrahepatic cholangiocarcinoma neuroendocrine carcinoma of the ampulla of Vater organoid culture
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Title	Establishment of Patient-Derived Organoids and Drug Screening for Biliary Tract Carcinoma
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