Dissecting gastric carcinogenesis: A novel approach using organoid models

• Project/Area Number: 20K07422
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Kunita Akiko 東京大学, 医学部附属病院, 特任講師 (50608768)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 胃癌 / オルガノイド / 腸上皮化生

Outline of Research at the Start

胃癌は日本人に多い癌であり胃癌制圧の為の基礎研究が急務である。これまでに多くの胃癌ゲノムデータが蓄積されているものの胃上皮培養法の欠如により胃発癌を端的に解析することが困難であり胃発癌分子機構は未解明であった。本研究ではオルガノイド、ゲノム編集技術などの先端研究手法を応用することにより胃発癌機構を解明する。特に胃発癌過程の中で腸上皮化生に注目し、オルガノイドモデルを用いて腸上皮化生の特性解析を行い癌化への関与の有無を明確に証明する。

Outline of Final Research Achievements

We have developed a method for establishing gastric organoids from resected gastric cancer specimens. The xenografts generated by transplanting tumor-derived organoids into the subcutaneous tissues of nude mice or SCID mice exhibited a similar structure to that of the original surgical specimens, thus establishing a gastric cancer model that reflects the characteristics of the surgical specimens.
In addition, we have improved the gene delivery method to organoids using lentivirus and established a method with higher cell viability and transfection efficiency. This method can be applied to study various pathological conditions of the stomach, including intestinal metaplasia and gastric cancer.

Academic Significance and Societal Importance of the Research Achievements

胃癌は日本人に多い癌であり胃癌制圧の為の基礎研究が急務である。これまでに多くの胃癌のゲノムデータが蓄積されているものの胃上皮培養法の欠如により胃発癌を端的に解析することが困難であり、胃発癌分子機構は未解明であった。本研究では新たな胃の病態モデルとしてオルガノイド技術の開発を行った。本技術により胃癌の病態に限らず他の臓器に応用することにより、あらゆる臓器の病態解明に結びつくと考えられる基盤を形成した。

Research Products

• [Journal Article] Tie2-Cre-Induced Inactivation of Non-Nuclear Estrogen Receptor-α Signaling Abrogates Estrogen Protection Against Vascular Injury (2023)
  • Author(s): Liu Pang-Yen、Fukuma Nobuaki、Hiroi Yukio、Kunita Akiko、Tokiwa Hiroyuki、Ueda Kazutaka、Kariya Taro、Numata Genri、Adachi Yusuke、Tajima Miyu、Toyoda Masayuki、Li Yuxin、Noma Kensuke、Harada Mutsuo、Toko Haruhiro、Ushiku Tetsuo、Kanai Yoshimitsu、Takimoto Eiki、Liao James K.、Komuro Issei
  • Journal Title: JACC: Basic to Translational Science Volume: 8 Issue: 1 Pages: 55-67
  • DOI: 10.1016/j.jacbts.2022.07.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of viral genome with altered immune microenvironment during tumour progression of <scp>Epstein‐Barr virus</scp> ‐associated gastric carcinoma (2023)
  • Author(s): Kondo Atsushi、Shinozaki‐Ushiku Aya、Rokutan Hirofumi、Kunita Akiko、Ikemura Masako、Yamashita Hiroharu、Seto Yasuyuki、Nagae Genta、Tatsuno Kenji、Aburatani Hiroyuki、Koinuma Daizo、Ushiku Tetsuo
  • Journal Title: The Journal of Pathology Volume: - Issue: 2 Pages: 124-136
  • DOI: 10.1002/path.6067
  • Peer Reviewed / Open Access
• [Journal Article] Microsatellite instability profiles of gastrointestinal cancers: comparison between non‐colorectal and colorectal origin (2022)
  • Author(s): Shinozaki‐Ushiku Aya、Kunita Akiko、Iwasaki Akiko、Kato Moe、Yamazawa Sho、Abe Hiroyuki、Ushiku Tetsuo
  • Journal Title: Histopathology Volume: 82 Issue: 3 Pages: 466-477
  • DOI: 10.1111/his.14830
  • Peer Reviewed
• [Journal Article] High-grade transformation of pancreatic neuroendocrine tumor associated with TP53 mutations: A diagnostic pitfall mimicking neuroendocrine carcinoma. (2022)
  • Author(s): Tanaka M, Shinozaki-Ushiku A, Kunita A, Yasunaga Y, Akamatsu N, Hasegawa K, Ushiku T.
  • Journal Title: Pathol Int. Volume: 72(8) Issue: 8 Pages: 411-418
  • DOI: 10.1111/pin.13252
  • Peer Reviewed
• [Journal Article] KRAS mutation in intrahepatic cholangiocarcinoma: linkage with metastasis-free survival and reduced E-cadherin expression. (2022)
  • Author(s): Tanaka M, Kunita A, Yamagishi M, Ishikawa S, Katoh H, Yamamoto H, Abe J, Arita J, Hasegawa K, Shibata T, and Ushiku T.
  • Journal Title: Liver Int. Volume: 42 Issue: 10 Pages: 2329-2340
  • DOI: 10.1111/liv.15366
  • Peer Reviewed
• [Journal Article] KRAS variant allele frequency, but not mutation positivity, associates with survival of patients with pancreatic cancer (2022)
  • Author(s): Suzuki T, Masugi Y, Inoue Y, Hamada T, Tanaka M, Takamatsu M, Arita J, Kato T, Kawaguchi Y, Kunita A, Nakai Y, Nakano Y, Ono Y, Sasahira N, Takeda T, Tateishi K, Uemura S, Koike K, Ushiku T, Takeuchi K, Sakamoto M, Hasegawa K, Kitago M, Takahashi Y, Fujishiro M.
  • Journal Title: Cancer Science Volume: - Issue: 9 Pages: 3097-3109
  • DOI: 10.1111/cas.15398
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced PD-L1 Expression in LMP1-Positive Cells of Epstein-Barr Virus-associated Malignant Lymphomas and Lymphoproliferative Disorders: A Single-cell Resolution Analysis with Multiplex Fluorescence Immunohistochemistry and In Situ Hybridization (2022)
  • Author(s): Ayako Kume, Aya Shinozaki-Ushiku, Akiko Kunita, Atsushi Kondo, Tetsuo Ushiku
  • Journal Title: American Journal of Surgical Pathology Volume: 46 Issue: 10 Pages: 1386-1396
  • DOI: 10.1097/pas.0000000000001919
  • Peer Reviewed
• [Journal Article] Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations (2022)
  • Author(s): Hongo Hiroki、Miyawaki Satoru、Teranishi Yu、Mitsui Jun、Katoh Hiroto、Komura Daisuke、Tsubota Kinya、Matsukawa Takashi、Watanabe Masakatsu、Kurita Masakazu、Yoshimura Jun、Dofuku Shogo、Ohara Kenta、Ishigami Daiichiro、Okano Atsushi、Kato Motoi、Hakuno Fumihiko、Takahashi Ayaka、Kunita Akiko、Ishiura Hiroyuki、et al.
  • Journal Title: Angiogenesis Volume: 26 Issue: 1 Pages: 37-52
  • DOI: 10.1007/s10456-022-09846-5
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced PD-L1 Expression in LMP1-Positive Cells of Epstein-Barr Virus-associated Malignant Lymphomas and Lymphoproliferative Disorders: A Single-cell Resolution Analysis with Multiplex Fluorescence Immunohistochemistry and In Situ Hybridization (2022)
  • Author(s): Kume Ayako, Shinozaki-Ushiku Aya, Kunita Akiko, Kondo Atsushi, Ushiku Tetsuo
  • Journal Title: American Journal of Surgical Pathology Volume: -
  • Peer Reviewed
• [Journal Article] KRAS variant allele frequency, but not mutation positivity, associates with survival of patients with pancreatic cancer (2022)
  • Author(s): Suzuki T, Masugi Y, Inoue Y, Hamada T, Tanaka M, Takamatsu M, Arita J, Kato T, Kawaguchi Y, Kunita A, Nakai Y, Nakano Y, Ono Y, Sasahira N, Takeda T, Tateishi K, Uemura S, Koike K, Ushiku T, Takeuchi K, Sakamoto M, Hasegawa K, Kitago M, Takahashi Y, Fujishiro M
  • Journal Title: Cancer Science Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis (2021)
  • Author(s): S Imai, T Ooki, N Murata-Kamiya, D Komura, K Tahmina, W Wu, Atsushi Takahashi-Kanemitsu, C T Knight, A Kunita, N Suzuki, A Del Valle, M Tsuboi, M Hata, Y Hayakawa, N Ohnishi, K Ueda, M Fukayama, T Ushiku, S Ishikawa, M Hatakeyama
  • Journal Title: Cell Host & Microbe Volume: 29 Issue: 6 Pages: 1-18
  • DOI: 10.1016/j.chom.2021.04.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human Leukocyte Antigen Class I Deficiency in Gastric Carcinoma (2021)
  • Author(s): Iwasaki Akiko、Shinozaki-Ushiku Aya、Kunita Akiko、Yamazawa Sho、Sato Yasuyoshi、Yamashita Hiroharu、Fukayama Masashi、Seto Yasuyuki、Ushiku Tetsuo
  • Journal Title: American Journal of Surgical Pathology Volume: 45 Issue: 9 Pages: 1213-1220
  • DOI: 10.1097/pas.0000000000001779
  • Peer Reviewed
• [Journal Article] Virus?host interactions in carcinogenesis of Epstein-Barr virus-associated gastric carcinoma: Potential roles of lost ARID1A expression in its early stage (2021)
  • Author(s): Abe Hiroyuki、Kunita Akiko、Otake Yuya、Kanda Teru、Kaneda Atsushi、Ushiku Tetsuo、Fukayama Masashi
  • Journal Title: PLOS ONE Volume: 16 Issue: 9 Pages: e0256440-e0256440
  • DOI: 10.1371/journal.pone.0256440
  • Peer Reviewed / Open Access
• [Journal Article] Helicobacter pylori CagA Induces BRCAness that Elicits Genome Instability Underlying Bacterial Hit-and-Run Gastric Carcinogenesis (2021)
  • Author(s): Satoshi Imai,Takuya Ooki, Naoko Murata-Kamiya, Daisuke Komura, Kamrunnesa Tahmina, Weida Wu, Atsushi Takahashi-Kanemitsu, Christopher Takaya Knight, Akiko Kunita, Nobumi Suzuki, Mayo Tsuboi, Masahiro Hata, Yoku Hayakawa, Naomi Ohnishi, Koji Ueda, Masashi Fukayama, Tetsuo Ushiku, Shumpei Ishikawa, Masanori Hatakeyama
  • Journal Title: Cell Host & Microbe Volume: -
  • Peer Reviewed
• [Journal Article] Programmed cell death protein 1/programmed death ligand 1 but not HER2 is a potential therapeutic target in gastric neuroendocrine carcinoma (2020)
  • Author(s): Yamashita Satoshi、Abe Hiroyuki、Kunita Akiko、Yamashita Hiroharu、Seto Yasuyuki、Ushiku Tetsuo
  • Journal Title: Histopathology Volume: 78 Issue: 3 Pages: 381-391
  • DOI: 10.1111/his.14230
  • Peer Reviewed
• [Journal Article] Exosomes of Epstein-Barr Virus-Associated Gastric Carcinoma Suppress Dendritic Cell Maturation (2020)
  • Author(s): Hinata Munetoshi、Kunita Akiko、Abe Hiroyuki、Morishita Yasuyuki、Sakuma Kei、Yamashita Hiroharu、Seto Yasuyuki、Ushiku Tetsuo、Fukayama Masashi
  • Journal Title: Microorganisms Volume: 8 Issue: 11 Pages: 1776-1776
  • DOI: 10.3390/microorganisms8111776
  • Peer Reviewed / Open Access
• [Presentation] RNAパネル検査に適した病理組織検体の取り扱い方法の最適化 (2022)
  • Author(s): 国田朱子,牛久綾,牛久哲男
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] 胃癌およびその他の消化管癌におけるマイクロサテライト不安定性検査の妥当性の比較 (2022)
  • Author(s): 牛久綾,国田朱子,牛久哲男
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] 膵癌におけるDroplet digital PCRを用いたKRAS変異検出: 多施設コホートにおける臨床検体の解析 (2022)
  • Author(s): 鈴木 辰典, 眞杉 洋平, 高松 学, 濱田 毅, 田中 麻理子, 国田 朱子, 中野 容, 立石 敬介, 小池 和彦, 牛久 哲男, 坂元 亨宇, 竹内 賢吾, 北郷 実, 藤城 光弘
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] TP53変異付加により悪性度が高まったと考えられる膵神経内分泌腫瘍の進展過程をとらえた剖検例 (2022)
  • Author(s): 近藤 篤史, 田中 麻理子, 大澤 一太, 牛久 綾, 国田 朱子, 安永 瑛一, 赤松 延久, 小峯 弓子, 鈴木 伸三, 藤城 光弘, 長谷川 潔, 牛久 哲男
  • Organizer: 第68回日本病理学会秋期特別総会
• [Presentation] 手つなぎ型胃癌とびまん型胃癌をつなぐゲノム異常 (2021)
  • Author(s): 六反啓文、国田朱子、柴田龍弘、牛久哲男
  • Organizer: 第110回日本病理学会総会
• [Presentation] マイクロサテライト不安定性小腸癌の臨床病理学的検討 (2021)
  • Author(s): 加藤萌、牛久綾、国田朱子、牛久哲男
  • Organizer: 第110回日本病理学会総会
• [Presentation] EBウイルス関連胃癌の進展過程で癌細胞からEBウイルスが消失した一例 (2021)
  • Author(s): 近藤篤史、六反啓文、国田朱子、牛久哲男
  • Organizer: 第 90 回 日本病理学会関東支部学術集会
• [Presentation] EBV partially positive gastric cancer: evidence of hit-and-run carcinogenesis? (2021)
  • Author(s): 近藤篤史、六反啓文、国田朱子、牛久綾、牛久哲男
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] 肝内胆管癌の臨床病理学的振る舞いにおけるKRASの意義 (2021)
  • Author(s): 田中麻理子、山岸誠、国田朱子、石川俊平、加藤洋人、長谷川潔、有田淳一、柴田龍弘、牛久哲男
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] 手つなぎ型胃癌のゲノム異常・病理像・進展形式の解析 (2021)
  • Author(s): 六反啓文、新井康仁、国田朱子、細田文恵、柴田龍弘、牛久哲男
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] 胃癌細胞におけるARID1A発現低下はEBVの感染を促進する (2020)
  • Author(s): 阿部浩幸、国田朱子、牛久哲男、深山正久
  • Organizer: 第109回日本病理学会総会
• [Presentation] AFP産生胃癌におけるHLA-G発現の検討 (2020)
  • Author(s): 深澤京、山澤翔、岩﨑晶子、国田朱子、牛久綾、牛久哲男
  • Organizer: 第109回日本病理学会総会