Understanding of invasion/metastasis mechanism in colorectal cancer using organoid technology

2016 Fiscal Year Annual Research Report

• Project/Area Number: 15K15297
• Research Institution: Keio University
• Principal Investigator: 佐藤 俊朗 慶應義塾大学, 医学部(信濃町), 准教授 (70365245)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: 大腸癌 / 浸潤 / 転移 / オルガノイド / 幹細胞

Outline of Annual Research Achievements

切除不能大腸がんは近年の化学療法の進歩により治療成績が向上しているが，依然としてがん死亡原因の上位にある。大腸がんによる死亡原因の多くはがんの浸潤・転移による体内の腫瘍量増大にあるといえる。一方，我々は，未だがんの浸潤・転移の完全な理解には至っておらず，その治療方法に結びついていない。特に，臨床で認められるがんの浸潤・転移を擬似化するモデルシステムがなく，そのメカニズム解明の足かせとなっている。我々は，患者由来大腸がんをin vitroで培養することができるオルガノイド培養技術を開発し，また，その超免疫不全マウスへの異種移植による浸潤・転移現象のモデル化に成功した。特に，転移巣由来のがんオルガノイドは異種移植系でも転移能を保持しており，がんの機能形質理解に極めて有用なモデルであることが示された。我々は，55ラインのヒト大腸腫瘍オルガノイドを樹立し，その遺伝子変異・発現変化と細胞生物学的な形質の変化への相関性を追求し，これまで困難であったGenotype-Phenotype連関を研究するプラットフォームを構築した。さらに，CRISPR-Cas9によるゲノム編集技術をがんオルガノイドへ応用することにより，プロスペクティブな遺伝子変異や遺伝子機能操作による細胞機能解析が可能となった。本研究により大腸がんの悪性度を規定する形質変化，特に浸潤・転移のメカニズムを追及する研究基盤が確立したといえる。様々な基礎研究に応用が可能な技術であり，今後の社会への高い波及効果が期待される。

Research Products

• [Journal Article] Visualization and Targeting of LGR5+ Human Colon Cancer Stem Cells (2017)
  • Author(s): Shimokawa M, Ohta Y, Nishikori S, Matano M, Takano A, Fujii M, Date S, Sugimoto S, Kanai T, Sato T
  • Journal Title: Nature Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1038/nature22081
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes. (2017)
  • Author(s): Kon S,Ishibashi K,Katoh H,Kitamoto S,Shirai T,Tanaka S,Kajita M,Ishikawa S,Yamauchi,Yako Ｙ, Kamasaki T,Nishikawa A,Kameda I, Maruyama T,Narumi R,Morita T,Sasaki Y,Enoki R,Honma S,Imamura H,Oshima M,Soga T,Miyazaki J,Duchen MR, Nam J,Onodera Y,Yoshioka S,Kikuta J,Ishii M, Imajo M,Nishida E,Fujioka Y,Ohba Y,Sato T
  • Journal Title: Nature Cell Biology Volume: 19 Pages: 530-541
  • DOI: 10.1038/ncb3509
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] IL-22BP dictates characteristics of Peyer's patch follicle-associated epithelium for antigen uptake (2017)
  • Author(s): Jinnohara T, Kanaya T, Hase K, Sakakibara S, Kato T, Tachibana N, Sasaki T, Hashimoto Y, Sato T, Watarai H, Kunisawa J, Shibata N, Williams I, Kiyono H, and Ohno H
  • Journal Title: J Exp Med Volume: 印刷中 Pages: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Expansion of adult human pancreatic tissue yields organoids harbouring progenitor cells with endocrine differentiation potential (2017)
  • Author(s): Loomans CJM, Giuliani NW, Balak J, Ringnalda F,van Gurp L, Huch M, Boj SF, Sato T, Kester L, de Sousa Lopes SMC, Roost MS, Bonner-Weir S, Engelse MA, Rabelink TJ, Heimberg H, Vries RGJ, van Oudenaarden A, Carlotti F, Clevers H, de Koning EJP
  • Journal Title: Science Translational Medicine Volume: 印刷中 Pages: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A Single Species of Clostridium Subcluster XIVa Decreased in Ulcerative Colitis Patients (2016)
  • Author(s): Takeshita K, Mizuno S, Mikami Y, Sujino T, Saigusa K, Matsuoka K, Naganuma M, Sato T, Takada T, Tsuji H, Kushiro A, Nomoto K, Kanai T
  • Journal Title: Inflamm Bowel Diｓ Volume: 22 Pages: 2802-2810
  • DOI: 10.1097/MIB.0000000000000972
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tissue-specific mutation accumulation in human adult stem cells during life (2016)
  • Author(s): Blokzijl F,de Ligt J,Jager M,Sasselli V,Roerink S,Sasaki N,Huch M,Boymans S,Kuijk E,Prins P, Nijman I,Martincorena I,Mokry M,Wiegerinck CL,Middendorp S,Sato T,Schwank G, Nieuwenhuis EES,Verstegen MMA,van der Laan LJW,de Jonge J,IJzermans JNM, Vries RG,van de Wetering M,Stratton MR,Clevers H,Cuppen E,van Boxtel R
  • Journal Title: Nature Volume: 538 Pages: 260-264
  • DOI: 10.1038/nature19768
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Zinc transporter SLC39A7/ZIP7 promotes intestinal epithelial self-renewal by resolving ER stress (2016)
  • Author(s): Ohashi W, Kimura S, Iwanaga T, Furusawa Y, Irie T, Izumi H, Watanabe T, Hijikata A, Hara T, Ohara O, Koseki H, Sato T, Robine S, Mori H, Hattori Y, Watarai H, Mishima K, Ohno H, Hase K, Fukada T
  • Journal Title: PLoS Genet Volume: 12 Pages: e1006349
  • DOI: 10.1371/journal.pgen.1006349
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mule Regulates the Intestinal Stem Cell Niche via the Wnt Pathway and Targets EphB3 for Proteasomal and Lysosomal Degradation (2016)
  • Author(s): Dominguez-Brauer C, Hao Z, Elia AJ, Fortin JM, Nechanitzky R, Brauer PM, Sheng Y, Mana MD, Chio II, Haight J, Pollett A, Cairns R, Tworzyanski L, Inoue S, Reardon C, Marques A, Silvester J, Cox MA, Wakeham A, Yilmaz OH, Sabatini DM, van Es JH, Clevers H, Sato T, Mak TW
  • Journal Title: Cell Stem Cell Volume: 19 Pages: 205-216
  • DOI: 10.1016/j.stem.2016.04.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements (2016)
  • Author(s): Fujii M, Shimokawa M, Date S, Takano A, Matano M, Ohta Y, Nanki K, Kawasaki K, Nakazato Y, Uraoka T, Watanabe T, Kanai T, Sato T
  • Journal Title: Cell Stem Cell Volume: 18 Pages: 827-838
  • DOI: 10.1016/j.stem.2016.04.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SETD7 controls intestinal regeneration and tumorigenesis by regulating Wnt/beta-catenin and Hippo/YAP signaling (2016)
  • Author(s): Oudhoff MJ, Braam MJS, Freeman SA, Wong D, Rattray DG, Want J, Antignano F, Snyder K, Refaeli I, Hughes MR, McNagny KM, Gold MR, Arrowsmith CH, Sato T, Rossi FMV, Tatlock JT, Owen D, Brown PJ, Zaph C
  • Journal Title: Developmental Cell Volume: 37 Pages: 47-57
  • DOI: 10.1016/j.devcel.2016.03.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 加齢・炎症ストレスの及ぼす腸管上皮幹細胞の分子遺伝学的変化．1PS18 ステムセルエイジング：老化の謎は解明できるか？ (2016)
  • Author(s): 佐藤俊朗，南木康作，下川真理子
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市）
  • Year and Date: 2016-11-30 – 2016-11-30
• [Presentation] Visualization of Human Colon Cancer Stem Cells Using Organoid Technology. Princess Takamatsu Cancer Research Fund. (2016)
  • Author(s): Toshiro Sato
  • Organizer: Current Status and Perspective of Cancer Stem Cell Research
  • Place of Presentation: Tokyo Palace Hotel(東京都千代田区)
  • Year and Date: 2016-11-08 – 2016-11-08
• [Presentation] Easy manipulation of the genome: CRISPR technology. Translational Basic Science Novel models for GI disease (2016)
  • Author(s): Toshiro Sato
  • Organizer: UEGW 2016
  • Place of Presentation: Ｖienna （Ａustria）
  • Year and Date: 2016-10-17 – 2016-10-17
• [Presentation] Disease modeling of human colorectal cancer. EMBO (2016)
  • Author(s): Toshiro Sato
  • Organizer: EMBL Symposium
  • Place of Presentation: Heidelberg（Germany）
  • Year and Date: 2016-10-15 – 2016-10-15
• [Presentation] Gut environments and human colorectal carcinogenesis. Symposium 17. The intestinal microflora and cancer (2016)
  • Author(s): Toshiro Sato, Shinya Sugimoto, Mami Matano
  • Organizer: The 75th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: PACIFICO Yokohama (Yokohama,Kanagawa)
  • Year and Date: 2016-10-08 – 2016-10-08
• [Presentation] ヒト大腸がん発がん・がん幹細胞のゲノム編集を用いた機能解析 (2016)
  • Author(s): 佐藤俊朗．太田悠木，股野麻未，藤井正幸，下川真理子
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-09-25 – 2016-09-25
• [Presentation] Disease Modeling of Colorectal Cancer Using Orgnaoids, Concurrent IV Disease modeling II. (2016)
  • Author(s): Toshiro Sato
  • Organizer: ISSCR 2016
  • Place of Presentation: San Francisco（America)
  • Year and Date: 2016-07-25 – 2016-07-25
• [Presentation] Disease modeling of colorectal cancer using organoids (2016)
  • Author(s): Toshiro Sato
  • Organizer: The 41st Naito Conference
  • Place of Presentation: CHATERAISE Gateaux Kingdom SAPPORO（Sapporo-shi, Hokkaido）
  • Year and Date: 2016-07-07 – 2016-07-07
• [Presentation] 腸管上皮オルガノイド培養の確立とその応用．特別企画２ 日本から世界に向けて発信されたトップ研究 (2016)
  • Author(s): 佐藤俊朗
  • Organizer: 第102回日本消化器病学会大会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-04-22 – 2016-04-22
• [Presentation] Intestinal Stem Cell Niche Signaling in Homeostatic and Diseased Epithelium. Session2. Gut homeostasis and IBD (2016)
  • Author(s): Toshiro Sato
  • Organizer: The 5th International Forum of the 102nd General Meeting of the Japanese Society of Gastroenterology
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-04-21 – 2016-04-21