1: An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping

Cell

2020 Oct 30;S0092-8674(20)31387-8. doi: 10.1016/j.cell.2020.10.023

Kenta Kawasaki, Kohta Toshimitsu, Mami Matano, Masashi Fujita , Masayuki Fujii, Kazuhiro Togasaki, Toshiki Ebisudani, Mariko Shimokawa, Ai Takano, Sirirat Takahashi, Yuki Ohta, Kosaku Nanki, Ryo Igarashi, Kazuhiro Ishimaru, Hiroki Ishida, Yasutaka Sukawa, Shinya Sugimoto, Yoshimasa Saito, Kazuhiro Maejima, Shota Sasagawa, Hwajin Lee, Hong-Gee Kim, Kyungsik Ha, Junko Hamamoto, Koichi Fukunaga, Aya Maekawa, Minoru Tanabe, Soichiro Ishihara, Yasuo Hamamoto, Hiroyuki Yasuda, Shigeki Sekine, Atsushi Kudo, Yuko Kitagawa, Takanori Kanai, Hidewaki Nakagawa, Toshiro Sato

Have you ever heard of the diseases neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC)? The incidence of NEC is 0.5-1 per 100,000 people. While the prognosis for gastrointestinal cancers is improving, NEC is a type of cancer with an extremely poor prognosis, with an untreated prognosis of only one month. Its treatment methods differ from those for gastrointestinal adenocarcinoma, and there has been a scarcity of cell lines for developing therapeutic drugs, leaving its pathophysiology, including genetic abnormalities, largely unknown. After I began treating NEC patients in the Department of Gastroenterology and Hepatology, research began to establish an animal model for this disease and to elucidate its pathophysiology. The technology that made this possible was the "organoid," which enables three-dimensional culture of tumor tissues obtained from patients. Although collecting cases was challenging, we received specimens from the Departments of Gastroenterology and Hepatology and surgery at our hospital, as well as from affiliated hospitals and other universities, and successfully established a total of 25 lines. Using this valuable resource, we conducted comprehensive molecular analyses, including whole-genome sequencing, in collaboration with RIKEN, and clarified the characteristic profiles of human hepatobiliary, pancreatic, and gastrointestinal neuroendocrine carcinomas, which had previously been unknown. Furthermore, using CRISPR/Cas9 genome editing technology, we successfully reconstructed neuroendocrine carcinoma from normal cells by artificially introducing the TP53 / RB1 gene mutations found in NEC into normal colonic epithelial cells and forcing the expression of six transcription factors. The results of this study can be said to have provided a research foundation for neuroendocrine carcinoma, for which research materials have been scarce worldwide. I am also very pleased that we were able to realize our desire to elucidate this disease at the bedside through Keio's strong network and fundamental analytical techniques, and I would like to express my heartfelt gratitude to the many doctors who cooperated with us.

(Kenta Kawasaki [90th graduating class] and Toshiro Sato [76th graduating class], Organoid Medicine)

J Am Coll Cardiol.

2020 Sep 15;76(11):1328-1340. doi: 10.1016/j.jacc.2020.07.037

Taku Inohara, Shun Kohsaka, John A Spertus, Frederick A Masoudi, John S Rumsfeld, Kevin F Kennedy, Tracy Y Wang, Kyohei Yamaji, Tetsuya Amano, Masato Nakamura

Blood.

2020;36(10):44-54. [Article] (Times Cited:)

Kanayama M, Izumi Y, Yamauchi Y, Kuroda S, Shin T, Ishikawa S, Sato T, Kajita M, Ohteki T.

Nature Chemical Biology .

2020;6():208-+.

Yamamoto J, Suwa T, Murase Y, Tateno S, Mizutome H, Asatsuma-Okumura T, Shimizu N, Kishi T, Momose S, Kizaki M, Ito T, Yamaguchi Y, Handa H.