Epigenetic regulation of pancreatic cancer stroma

• Project/Area Number: 20K08324
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Sato Tatsuya 東京大学, 医学部附属病院, 助教 (60843753)
• Co-Investigator(Kenkyū-buntansha): 立石 敬介 東京大学, 医学部附属病院, 届出研究員 (20396948)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 膵癌 / CAF / pancreatic cancer

Outline of Research at the Start

腫瘍内の間質細胞や免疫細胞を含めた微小環境は癌細胞自体の増殖や悪性度に影響を及ぼ
し、薬剤による治療抵抗性などにも関連する。豊富な腫瘍間質を有する膵癌組織において癌随伴性線維芽細胞CAFに多様性と可塑性があることが明らかとなったが、その多様なプロファイルや相互の可塑性が癌の進展にどのように寄与するのかは明らかでない。前研究で膵癌CAFの活性化にエピゲノム制御機構が重要であることをヒト膵癌由来PDXを用いて明らかにした。本研究では、ヒト膵癌におけるCAFの機能的活性化のみならず、その多様性と相互の可塑性が腫瘍自体の悪性度に及ぼす影響を、エピゲノムとの関連とともに検討する。

Outline of Final Research Achievements

Although it has become clear that cancer-associated fibroblast CAFs in pancreatic cancer tissue are diverse and plastic, it is not clear how their diverse profiles and mutual plasticity contribute to cancer progression. It is conceivable that these diverse CAF clusters are dynamically migratory to each other, and that epigenomic regulatory mechanisms that play an important role in cell plasticity may also be associated with the regulation of their diversity and indirectly contribute to the malignant potential of the tumors themselves.
In this study, we investigated not only the functional activation of CAFs in human pancreatic cancer, but also the effects of their diversity and mutual plasticity on the malignant potential of the tumor itself, as well as their relationship with epigenomic regulation of gene expression.

Academic Significance and Societal Importance of the Research Achievements

腫瘍内の間質細胞や免疫細胞を含めた微小環境が癌細胞自体の増殖や悪性度に影響を及ぼし、例えばそれは薬剤による治療抵抗性などにも関連する。豊富な線維性間質によるDesmoplasiaをその病理学的特徴とする膵癌では、その腫瘍組織の大部分を占める活性化したCAFや免疫細胞などの間質系細胞と、産生される膠原線維や増殖因子が腫瘍促進的な微小環境を構成し、膵癌細胞自体の増殖や各種治療に対する抵抗性を誘導すると考えられてきた。本研究はその膵癌腫瘍組織の重要性におけるエピゲノム制御の関係を明らかにする学術的意義を有する。

Research Products

• [Journal Article] Early skeletal muscle mass decline is a prognostic factor in patients receiving gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer: a retrospective observational study (2023)
  • Author(s): Suzuki Yukari、Saito Kei、Nakai Yousuke、Oyama Hiroki、Kanai Sachiko、Suzuki Tatsunori、Sato Tatsuya、Hakuta Ryunosuke、Ishigaki Kazunaga、Saito Tomotaka、Hamada Tsuyoshi、Takahara Naminatsu、Tateishi Ryosuke、Fujishiro Mitsuhiro
  • Journal Title: Supportive Care in Cancer Volume: 31 Issue: 3
  • DOI: 10.1007/s00520-023-07659-w
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Outcomes of Intraductal Papillary Mucinous Neoplasms With Dilatation of the Main Pancreatic Duct (2023)
  • Author(s): Hamada Tsuyoshi、Oyama Hiroki、Nakai Yousuke、Tateishi Keisuke、Ushiku Tetsuo、Hasegawa Kiyoshi、Fujishiro Mitsuhiro
  • Journal Title: Clinical Gastroenterology and Hepatology Volume: - Issue: 7 Pages: 1792-1801.e3
  • DOI: 10.1016/j.cgh.2023.01.032
  • 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