Stratification and optimization of pancreatic cancer treatment based on chromatin dynamics

• Project/Area Number: 21K15966
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Kato Hiroyuki 東京大学, 医学部附属病院, 特任臨床医 (70829788)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 膵管内乳頭粘液性腫瘍(IPMN) / 膵臓癌 / オルガノイド / 次世代シーケンサー / クロマチン / エピゲノム / ゲノム構造

Outline of Research at the Start

各種膵腫瘍の病態理解における分子学的層別化と、治療における最適化は喫緊の課題である。近年、大規模なゲノム解析から膵癌にもサブタイプが存在することが報告されているが、治療への実装という点では未解決の点も多い。
我々は細胞固有の表現型を規定するクロマチン動態を詳細に解析することで膵腫瘍を層別化し、各群の生存に不可欠なエピゲノム標的を同定することができれば、特異的な治療法を提唱できるのではないかと考えた。
本研究では患者由来膵腫瘍オルガノイドライブラリーを用いて膵発癌過程や癌固有のクロマチン動態と癌の生存能との関わりを明らかにすることで、治療標的としての実装可能性を検証していく。

Outline of Final Research Achievements

Unraveling the pathogenesis of various pancreatic tumors is an urgent issue for their treatment optimization. Among them, intraductal papillary mucinous tumor (IPMN) is one of the precursor lesions in pancreatic cancers, which is often identified as a pancreatic cyst in health checkups. Although the number of patients with IPMN is increasing, no treatment has been established to prevent IPMN carcinogenesis other than surgical resection. Therefore, understanding of the tumor progression process of IPMN has been warranted.
To achieve this, we have established a series of original patient derived IPMN organoids. By applying cutting-edge genomic and epigenomic analyses to these models, we have identified that IPMN have distinct epigenomic profiles with characteristic addictive behaviors supported by MNX1-HNF1B axis, implying a feasibility for therapeutic implementation in this disease. These findings may contribute to the control of IPMN pathogenesis.

Academic Significance and Societal Importance of the Research Achievements

我々はIPMN の多様な消化器臓器系譜を模して進展する臨床病理学的特徴に着目し、細胞系譜を司るエピゲノムにこそ、その本質が潜在すると仮説立てることで疾患の本質を追求するに至った。臨床に則した視点と、患者検体の有効活用、先端技術の融和による病態解明手法の有用性を提唱するとともに、蓄積したオミクスデータはIPMN の悪性化過程の解明、並びに新規治療標的を探索する重要な資源になると考える。
加えて、本研究を足掛かりに前癌段階のIPMN時点での腫瘍の脆弱性を検討することの重要性や、発癌予防へ向けたIPMN診療のパラダイムシフトを提案する一助となればと考える。

Research Products

• [Journal Article] 膵管内乳頭粘液性腫瘍の解明 - IPMNオルガノイドの樹立 - (2023)
  • Author(s): 加藤裕之, 立石敬介, 藤城光弘
  • Journal Title: 膵臓 Volume: 38 Pages: 10-18
  • Peer Reviewed
• [Journal Article] HNF1B‐driven three‐dimensional chromatin structure for molecular classification in pancreatic cancers (2022)
  • Author(s): Kato Hiroyuki、Tateishi Keisuke、Iwadate Dosuke、Yamamoto Keisuke、Fujiwara Hiroaki、Nakatsuka Takuma、Kudo Yotaro、Hayakawa Yoku、Ijichi Hideaki、Otsuka Motoyuki、Kishikawa Takahiro、Takahashi Ryota、Miyabayashi Koji、Nakai Yousuke、Hirata Yoshihiro、Toyoda Atsushi、Morishita Shinichi、Fujishiro Mitsuhiro
  • Journal Title: Cancer Science Volume: 114 Issue: 4 Pages: 1672-1685
  • DOI: 10.1111/cas.15690
  • Peer Reviewed / Open Access
• [Journal Article] MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages (2022)
  • Author(s): Kato H, Tateishi K, Fujiwara H, Nakatsuka T, Yamamoto K, Kudo Y, Hayakawa Y, Nakagawa H, Tanaka Y, Ijichi H, Otsuka M, Iwadate D, Oyama H, Kanai S, Noguchi K, Suzuki T, Sato T, Hakuta R, Ishigaki K, Saito K, Saito T, Takahara N, Kishikawa T, Hamada T, Takahashi R, Miyabayashi K, et al.
  • Journal Title: Gastroenterology Volume: 162 Issue: 4 Pages: 1272-1287
  • DOI: 10.1053/j.gastro.2021.12.254
  • Peer Reviewed / Open Access
• [Presentation] Mapping the chromatin profiles of IPMN lineages to unveil their biological vulnerabilities (2022)
  • Author(s): Hiroyuki Kato
  • Organizer: United European Gastroenterology Week
  • Int'l Joint Research / Invited
• [Presentation] Hi-C analysis in patient-derived organoids reveals the impact of three-dimensional chromatin structures on pancreatic cancer transcriptional subtypes (2022)
  • Author(s): Hiroyuki Kato; Dosuke Iwadate; Keisuke Yamamoto; Hiroaki Fujiwara; Hideaki Ijichi; Mitsuhiro Fujishiro; Keisuke Tateishi
  • Organizer: AACR Special Conference: Pancreatic cancer
  • Int'l Joint Research
• [Presentation] Large-scale genome structure dynamics shapes transcriptional subtype in pancreatic cancer (2022)
  • Author(s): Hiroyuki Kato, Keisuke Tateishi, Dosuke Iwadate, Hiroaki Fujiwara, Keisuke Yamamoto, Takahiro Kishikawa, Koji Miyabayashi, Ryota Takahashi, Hideaki Ijichi, Yousuke Nakai, Mitsuhiro Fujishiro
  • Organizer: The Joint Congress of the 26th Meeting of International Association of Pancreatology and the 53rd Annual Meeting of Japan Pancreas Society
  • Int'l Joint Research
• [Presentation] クロマチン動態から探る膵腫瘍の層別化 (2021)
  • Author(s): 加藤 裕之
  • Organizer: 第52回日本膵臓学会大会
• [Presentation] A multi-omics study in patient-derived organoids reveals MNX1-HNF1B axis to be indispensable for intraductal mucinous papillary neoplasm lineages (2021)
  • Author(s): Hiroyuki Kato
  • Organizer: 2021 AACR VIRTUAL SPECIAL CONFERENCE: PANCREATIC CANCER
  • Int'l Joint Research
• [Presentation] オルガノイドを用いた膵腫瘍の進展機構の検討 (2021)
  • Author(s): 加藤 裕之
  • Organizer: 2021年度日本消化器関連学会（JDDW 2021）
• [Remarks] 膵管内乳頭粘液性腫瘍（IPMN）に重要な腫瘍進展機構を新たに同定
  • URL: https://www.h.u-tokyo.ac.jp/participants/research/saishinkenkyu/20211223.html
• [Remarks] 【プレスリリース】膵管内乳頭粘液性腫瘍（IPMN）に重要な腫瘍進展機構を新たに同定
  • URL: https://www.h.u-tokyo.ac.jp/press/20211223.html