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Elucidation of the mechanism of intractability of pancreatobiliary cancers using patients-derived organoids

Research Project

Project/Area Number 23K24101
Project/Area Number (Other) 22H02839 (2022-2023)
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeMulti-year Fund (2024)
Single-year Grants (2022-2023)
Section一般
Review Section Basic Section 49020:Human pathology-related
Research InstitutionTohoku University

Principal Investigator

古川 徹  東北大学, 医学系研究科, 教授 (30282122)

Co-Investigator(Kenkyū-buntansha) 木下 賢吾  東北大学, 情報科学研究科, 教授 (60332293)
海野 倫明  東北大学, 医学系研究科, 教授 (70282043)
Project Period (FY) 2022-04-01 – 2026-03-31
Project Status Granted (Fiscal Year 2024)
Budget Amount *help
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2025: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2024: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Keywords膵臓がん / 胆道がん / オルガノイド / ゲノム / 化学療法 / 膵管内腫瘍 / がん関連線維芽細胞 / 分子標的
Outline of Research at the Start

本研究は実臨床において一定のプロトコールの下よくコントロールされて実施された術前化学療法後に切除された膵臓胆道がんの化学療法奏功例と非奏功例におけるがんのゲノムや遺伝子発現、及び、ホストである患者のゲノム多型を解析することで化学療法感受性・抵抗性に関与する分子を抽出し、オルガノイド培養細胞の樹立、使用を含む機能解析を行なって化学療法感受性への関与を明らかにし、それらをバイオマーカーとする化学療法感受性予測、標的化による化学療法抵抗性克服法の開発を行うことで膵胆道がんの予後改善に寄与する。

Outline of Annual Research Achievements

1. 化学療法を施行した例を含む膵・胆道がん外科切除患者から至適培養条件の検討を行いながら継代可能な腫瘍オルガノイド及びがん関連線維芽細胞(CAF)の培養細胞株を樹立し、ゲノム解析、トランスクリトーム解析、病理組織学的解析を行ってその遺伝子型、表現型を検討した。腫瘍オルガノイドのゲノム・トランスクリプトーム解析から候補となる治療標的の同定及びそれに対する分子標的薬のオルガノイドに対する作用を、特徴的な遺伝子異常に基づく合成致死治療法の開発を主眼に置きながら検討した。腫瘍オルガノイドとCAFの3次元マトリックス中での培養を行い、それらの相互作用をin vitroで解析可能であることを確認し、その相互作用の詳細について検討した。
2.膵がん切除後の残膵に発生した膵がん切除例を集積し、先行膵がんと残膵がんとのゲノム解析による比較を行って残膵がん発生の分子機序について検討した。
3. 増殖・浸潤様式が不明である膵管内乳頭粘液性腫瘍(IPMN)についてオルガノイドを樹立し、そのマトリックス中での増殖様式を解析し、IPMNオルガノイドにおける粘液分泌機序、浸潤機序の検討を行なった。
4. 病態が不明な膵腫瘍である膵管内オンコサイト型腫瘍(IOPN)のドライバーであるATP1B1::PRKACA/B, DNAJB1::PRKACA融合遺伝子がIPMNにしばしば部分的に認められるオンコサイト型腫瘍の発生において、既存のIPMNに遺伝子融合が新たに蓄積することによって生じていることを明らかにし、IPMNがIOPNの表現型を持つ腫瘍に変化しうることを示して、論文発表を行なった。この結果は、IPMNとIOPNの病理学的な異同の概念にパラダイムシフトをもたらすものと考えられる。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

当初計画で予定していた患者由来オルガノイドを用いた多角的解析を進めることができた。膵・胆道がんオルガノイドとCAFとの関連についてデータを得ることができ、また、残膵がん発生の分子機序解明、及び、詳細な増殖浸潤機序、粘液分泌機序が不明であるIPMNの解析、さらには、病態が不明でIPMNとの異同について議論のあるIOPNの発生進展機序に重要な知見を得ることができ、当初目的に沿って膵・胆道がんの治療抵抗性機序解明に多角的にアプローチできている。

Strategy for Future Research Activity

患者由来オルガノイドを用いた多角的解析を中心に研究を続行していく。具体的には、患者由来膵・胆道がんオルガノイドとCAFとの相互作用における分子発現関連の空間トランスクリプトームによる解析、マトリックス中での増殖、浸潤、粘液分泌機序の機能的解析、ゲノム解析に基づく個別化分子標的治療法の開発を進める。

Report

(2 results)
  • 2023 Annual Research Report
  • 2022 Annual Research Report
  • Research Products

    (32 results)

All 2024 2023 2022 Other

All Int'l Joint Research (5 results) Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 4 results) Presentation (21 results) (of which Int'l Joint Research: 14 results,  Invited: 4 results)

  • [Int'l Joint Research] Johns Hopkins University/Memorial Sloan Kettering Cancer Center/Massachusetts General Hospital(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] University of Verona(イタリア)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] University of Korc(トルコ)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Asan Medical Center(韓国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] University of Utrecht(オランダ)

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Gene Rearrangement and Expression of PRKACA and PRKACB Govern Morphobiology of Pancreatobiliary Oncocytic Neoplasms2024

    • Author(s)
      Itoh T, Omori Y, Seino M, Hirose K, Date F, Ono Y, Mizukami Y, Aoki S, Ishida M, Mizuma M, Morikawa T, Higuchi R, Honda G, Okamura Y, Kinoshita K, Unno M, Furukawa T.
    • Journal Title

      Modern Pathology

      Volume: 37 Issue: 1 Pages: 100358-100358

    • DOI

      10.1016/j.modpat.2023.100358

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] GATA6 and CK5 Stratify the Survival of Patients With Pancreatic Cancer Undergoing Neoadjuvant Chemotherapy2023

    • Author(s)
      Kokumai Takashi、Omori Yuko、Ishida Masaharu、Ohtsuka Hideo、Mizuma Masamichi、Nakagawa Kei、Maeda Chiho、Ono Yusuke、Mizukami Yusuke、Miura Shin、Kume Kiyoshi、Masamune Atsushi、Morikawa Takanori、Unno Michiaki、Furukawa Toru
    • Journal Title

      Modern Pathology

      Volume: 36 Issue: 5 Pages: 100102-100102

    • DOI

      10.1016/j.modpat.2023.100102

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular comparison of concurrent components of high-grade dysplasia, adenocarcinoma, and sarcomatoid carcinoma in a case of sarcomatoid carcinoma of the gallbladder2023

    • Author(s)
      Hirose Katsuya、Omori Yuko、Ono Yusuke、Mizukami Yusuke、Kaneko Yoshiki、Maruyama Tsunehiko、Ohtani Haruo、Furukawa Toru
    • Journal Title

      Virchows Archiv

      Volume: 99 Issue: 2 Pages: 99-99

    • DOI

      10.1007/s00428-023-03524-7

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Long Non-Coding RNAs Associated with Mitogen-Activated Protein Kinase in Human Pancreatic Cancer2023

    • Author(s)
      Ishikawa Tomohiko、Fukushige Shinichi、Saiki Yuriko、Hirose Katsuya、Hiyoshi Takako、Ogawa Takenori、Katori Yukio、Furukawa Toru
    • Journal Title

      Cancers

      Volume: 15 Issue: 1 Pages: 303-303

    • DOI

      10.3390/cancers15010303

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mechanisms of development and progression of pancreatic neoplasms.2022

    • Author(s)
      Furukawa T.
    • Journal Title

      Pathology International

      Volume: 72 Issue: 11 Pages: 529-540

    • DOI

      10.1111/pin.13272

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Application of Patient-Derived Cancer Organoids to Personalized Medicine2022

    • Author(s)
      Masahiro Shiihara
    • Journal Title

      journal of personalized medicine

      Volume: 12 Issue: 5 Pages: 789-789

    • DOI

      10.3390/jpm12050789

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 膵癌前駆病変の分子病理2024

    • Author(s)
      古川 徹
    • Organizer
      第37回日本糖尿病・肥満動物学会年次学術集会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Molecular Mechanisms of Precursor Lesions Progressing to Pancreatic Cancer2024

    • Author(s)
      古川徹
    • Organizer
      第113回日本病理学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] ディープラーニングによる腹腔洗浄細胞診標本を用いた膵癌患者の予後予測2024

    • Author(s)
      野口彩、沼田康志、菅原隆譲、三浦弘守、石田晶玄、堂地大輔、前田一郎、海野倫明、山本陽一朗、古川徹.
    • Organizer
      第113回日本病理学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 高異型度PanIN/膵上皮内癌・小径膵癌の分子進化モデル2024

    • Author(s)
      伊藤泰斗、大森優子、小野裕介、高橋賢治、岡村容伸、木下賢吾、正宗淳、海野倫明、水上裕輔、古川徹
    • Organizer
      第113回日本病理学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Relevance of genomic profiling of pancreatobiliary cancers in clinical oncology.2023

    • Author(s)
      Furukawa T, Shirota H, Ishioka C
    • Organizer
      第61回日本癌治療学会学術集会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 残膵癌における先行膵癌との分子病理学的および臨床病理学的検討2023

    • Author(s)
      鈴木修司,大森優子,廣瀬勝也,小野裕介,唐崎秀則,下田貢,永川裕一,水上裕輔,古川徹
    • Organizer
      第54回日本膵臓学会大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Exploring the growth morphology and mucus secretion mechanism of IPMN using patients-derived organoids and comprehensive genome analysis.2023

    • Author(s)
      Shiihara M, Takahashi K, Ishikawa T, Omori Y, Hirose K, Nakagawa K, Mizuma M, Ohtsuka H, Motoi F, Unno M, Okamura Y, Kinoshita K, Furukawa T.
    • Organizer
      A Joint International Conference Pancreas 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Lessons Learned from Mistakes Made In the Interpretation of Small Biopsies and Cytologic Samples from the Pancreatobiliary Tract and Ampulla.2023

    • Author(s)
      Furukawa T.
    • Organizer
      112th Annual Meeting of the United States and Canadian Academy of Pathology.
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Molecular Phenotyping and the Combinatorial System by the Number of Accumulated Gene Alterations of Intraductal Papillary Mucinous Neoplasms Stratifies the Risk of Invasion and Outcome: New Insight for Management Strategy.2023

    • Author(s)
      Omori Y, Ono Y, Kokumai T, Date F, Higuchi R, Honda G, Mizukami Y, Morikawa T, Unno M, Furukawa T.
    • Organizer
      112th Annual Meeting of the United States and Canadian Academy of Pathology.
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Prognostic Performance of Microscopic Size Measurements in Small Invasive Carcinomas Arising in Intraductal Papillary Mucinous Neoplasms (IPMNs) of the Pancreas.2023

    • Author(s)
      Zhang ML, Omori Y, Hong SM, Ideno N, Date K, Missael Rocha Castellanous D, Shroff S, Furukawa T, Fernadez-del Castillo C, Mino-Kenudson M.
    • Organizer
      112th Annual Meeting of the United States and Canadian Academy of Pathology. 2023年3月11-17日 New Orleans, LO, USA Poster
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Whole exome sequencing of familial pancreatic cancer cases in Japan.2022

    • Author(s)
      Furukawa T.
    • Organizer
      第81回日本癌学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Pathological aspects. International Consensus Meeting Management of IPMN and MCN.2022

    • Author(s)
      Furukawa T.
    • Organizer
      International Association of Pancreatology and Japan Pancreas Society Meeting 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Three molecular development pathways of remnant pancreatic cancer impact survival after resection.2022

    • Author(s)
      Suzuki S, Omori Y, Hirose K, Ono Y, Karasaki H, Shimoda M, Nagakawa Y, Tsuchida A, Mizukami Y, Furukawa T.
    • Organizer
      nternational Association of Pancreatology and Japan Pancreas Society Meeting 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Interobserver agreement on biopsy-based diagnosis of autoimmune pancreatitis.2022

    • Author(s)
      Notohara K, Kamisawa T, Furukawa T, Fukushima N, Ikeura T, Kawa S, Okazaki K.
    • Organizer
      International Association of Pancreatology and Japan Pancreas Society Meeting 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Molecular Phenotypic Risk Stratification of Intraductal Papillary Mucinous Neoplasms.2022

    • Author(s)
      Omori Y, Ono Y, Morikawa T, Date F, Higuchi R, Honda G, Karasaki H, Mizukami Y, Unno M, Furukawa T.
    • Organizer
      International Association of Pancreatology and Japan Pancreas Society Meeting 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] STK11-aletered intraductal papillary mucinous neoplasms develop characteristic clinico-patho-biology.2022

    • Author(s)
      Omori Y, Ono Y, Itoh T, Date F, Morikawa T, Motoi F, Higuchi R, Honda G, Karasaki H, Mizukami Y, Unno M, Furukawa T.
    • Organizer
      International Association of Pancreatology and Japan Pancreas Society Meeting 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Characteristics of growth and mucus secretion of patient-derived organoids may substantiate invasive phenotypes of IPMN.2022

    • Author(s)
      Shiihara M, Ishikawa T, Yoshida T, Omori Y, Hirose K, Morikawa T, Nakagawa K, Mizuma M, Otsuka H, Motoi F, Unno M, Okamura Y, Kinoshita K, Furukawa T.
    • Organizer
      International Association of Pancreatology and Japan Pancreas Society Meeting 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Rearrangement and expression of PRKACA/B governs phenotypes of pancreato-biliary oncocytic neoplasms.2022

    • Author(s)
      Itoh T, Omori Y, Seino M, Hirose K, Date F, Ono Y, Mizukami Y, Mizuma M, Morikawa T, Higuchi R, Honda G, Unno M, Furukawa T.
    • Organizer
      International Association of Pancreatology and Japan Pancreas Society Meeting 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Expression phenotypes of GATA6 and CK5 stratify the survival of pancreatic cancer.2022

    • Author(s)
      Kokumai T, Omori Y, Ishida M, Date F, Inoue K, Douchi D, Nakayama S, Miura T, Maeda S, Masuda K, Takikawa T, Miura S, Kume K, Ohtsuka H, Mizuma M, Nakagawa K, Morikawa T, Masamune A, Unno M, Furukawa T.
    • Organizer
      International Association of Pancreatology and Japan Pancreas Society Meeting 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Dual specificity phosphatase 6 deficiency improves insulin sensitivity and protects against obesity in mice.2022

    • Author(s)
      Jiang C, Saiki Y, Furukawa T.
    • Organizer
      International Association of Pancreatology and Japan Pancreas Society Meeting 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Intraductal neoplasms of the pancreas are precursor lesions of the pancreatic cancer.2022

    • Author(s)
      Furukawa T.
    • Organizer
      7th Japanese Cancer Association and American Association for Cancer Research Special Joint Conference. The Latest Advances in Pancreatic Cancer Research: From Basic Science to Therapeutics.
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited

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Published: 2022-04-19   Modified: 2024-12-25  

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