Structural analysis of tumor hotspots, an epithelial tissue-intrinsic novel oncogenic niche

• Project/Area Number: 18KK0234
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Kyoto University (2019-2021); Hokkaido University (2018)
• Principal Investigator: Tamori Yoichiro 京都大学, 医学研究科, 准教授 (10717325)
• Co-Investigator(Kenkyū-buntansha): 石原 誠一郎 北海道大学, 先端生命科学研究院, 助教 (10719933) ; 昆 俊亮 東京理科大学, 研究推進機構生命医科学研究所, 講師 (70506641)
• Project Period (FY): 2018-10-09 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2021: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2020: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2018: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: 腫瘍形成 / 上皮組織 / 細胞増殖 / 組織構造 / 腫瘍浸潤 / 平面内細胞極性 / ショウジョウバエ / 浸潤性

Outline of Final Research Achievements

In the experimental studies using Drosophila wing imaginal epithelia as a model, we found that oncogenic mutant cells break the basement membrane and begin their invasive behavior into the stroma in microenvironments (invasion hotspots) scattered within the epithelial tissue. Analysis using the TCPD program (a program developed in this study to predict structural singularities in tissues) based on fluid analysis revealed that the locations detected as tissue confluence points (saddle points and sink points) in the tissues coincided with these invasion hotspots. These data indicate a novel idea that cancer cell invasion into the stroma starts from structural singularities intrinsic to epithelial tissues. Our experiments using a mouse model also showed that a similar phenomenon might be able to occur in mammalian tissues as well.

Academic Significance and Societal Importance of the Research Achievements

がん細胞の上皮層から間質への浸潤は、内在的に他とは異なる組織構造を持つ微小環境（浸潤ホットスポット）から始まることを発見した。このような現象は今までに報告されておらず、この研究成果は腫瘍悪性化プロセスの基本理解に新しい視点を提供するものとなる。また、流体解析を応用したTCPDプログラム（組織内の構造的特異点を予測するプログラム）を用いて、ショウジョウバエの上皮組織において浸潤ホットスポットが検出できることを示した。生体組織の顕微鏡画像から腫瘍の浸潤が始まる場所を予測できるこのようなプログラムはこれまでにないものであり、将来的には全く新しい予防的な病理診断法の開発につながることが期待される。

Research Products

• [Int'l Joint Research] University of California, Los Angeles/Tulane University(米国)
• [Int'l Joint Research] University of California, Los Angeles(米国)
• [Int'l Joint Research] UCLA/Tulane University(米国)
• [Journal Article] Matrix stiffness contributes to cancer progression by regulating transcription factors (2022)
  • Author(s): Seiichiro Ishihara, Hisashi Haga
  • Journal Title: Cancers Volume: 14 Issue: 4 Pages: 1049-1049
  • DOI: 10.3390/cancers14041049
  • Peer Reviewed / Open Access
• [Journal Article] 腫瘍ホットスポット：組織内在性のがん原性ニッチ (2021)
  • Author(s): 小林 怜, 田守 洋一郎
  • Journal Title: Precision Medicine Volume: 4 Pages: 90-95
  • NAID: 40022508085
• [Journal Article] Tumor-Cell Invasion Initiates at Invasion Hotspots, an Epithelial Tissue-Intrinsic Microenvironment (2021)
  • Author(s): Rei Kobayashi, Hiroaki Takishima, Sheng Deng, Yasuyuki Fujita, Yoichiro Tamori
  • Journal Title: bioRxiv Volume: 2021.09.28 Pages: 462102-462102
  • DOI: 10.1101/2021.09.28.462102
  • Open Access
• [Journal Article] Sequential oncogenic mutations influence cell competition (2021)
  • Author(s): Kohashi Koki、Mori Yusuke、Narumi Rika、Kozawa Kei、Kamasaki Tomoko、Ishikawa Susumu、Kajita Mihoko、Kobayashi Rei、Tamori Yoichiro、Fujita Yasuyuki
  • Journal Title: Current Biology Volume: 31 Issue: 18 Pages: 3984-3995
  • DOI: 10.1016/j.cub.2021.06.064
  • Peer Reviewed / Open Access
• [Journal Article] Soft surfaces promote astrocytic differentiation of mouse embryonic neural stem cells via dephosphorylation of MRLC in the absence of serum (2021)
  • Author(s): Hiroshi Oyama, Akihiro Nukuda, Seiichiro Ishihara, Hisashi Haga
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 19574-19574
  • DOI: 10.1038/s41598-021-99059-5
  • Peer Reviewed / Open Access
• [Journal Article] Cell competition-induced apical elimination of transformed cells, EDAC, orchestrates the cellular homeostasis (2021)
  • Author(s): Kon Shunsuke、Fujita Yasuyuki
  • Journal Title: Developmental Biology Volume: 476 Pages: 112-116
  • DOI: 10.1016/j.ydbio.2021.03.015
  • Peer Reviewed / Open Access
• [Journal Article] 腫瘍ホットスポット : 組織内在性のがん原性ニッチ (2021)
  • Author(s): 小林怜, 田守洋一郎
  • Journal Title: 細胞 Volume: 53 Pages: 121-125
  • NAID: 40022508085
• [Journal Article] 細胞競合における機械刺激応答を介した組織修復 (2020)
  • Author(s): 奈良真吾, 田守洋一郎
  • Journal Title: 医学のあゆみ Volume: 274 Pages: 434-441
• [Journal Article] Tissue homeostasis through cell competition and compensatory cell growth (2019)
  • Author(s): 田守 洋一郎、藤田 恭之
  • Journal Title: 生化学 Volume: 91 Issue: 2 Pages: 147-158
  • DOI: 10.14952/SEIKAGAKU.2019.910147
  • NAID: 40021942451
  • ISSN: 0037-1017
  • Year and Date: 2019-04-25
  • Peer Reviewed
• [Journal Article] The initial stage of tumorigenesis in Drosophila epithelial tissues (2019)
  • Author(s): Yoichiro Tamori
  • Journal Title: Advances in Experimental Medicine and Biology Volume: 1167 Pages: 87-103
  • DOI: 10.1007/978-3-030-23629-8_5
  • ISBN: 9783030236281, 9783030236298
  • Peer Reviewed
• [Presentation] がんの進行における必然性と倍数性 (2022)
  • Author(s): 田守 洋一郎
  • Organizer: 第9回細胞競合コロキウム
• [Presentation] 組織内在性の微小環境に依存したがん細胞の浸潤性獲得 (2022)
  • Author(s): 小林 怜, 藤田 恭之, 田守 洋一郎
  • Organizer: 第9回細胞競合コロキウム
• [Presentation] Polyploidy in tumor cell invasion (2022)
  • Author(s): Sheng Deng, 池口 純規, 藤田 恭之, 田守 洋一郎
  • Organizer: 第9回細胞競合コロキウム
• [Presentation] がん細胞が誕生したときの生体内反応 (2021)
  • Author(s): 昆 俊亮
  • Organizer: 第５３回 フォーラム富山「創薬」
  • Invited
• [Presentation] Tumor-cell invasion initiates at invasion hotspots, an epithelial tissue-intrinsic microenvironment (2021)
  • Author(s): Sheng Deng
  • Organizer: 第14回日本ショウジョウバエ研究集会
• [Presentation] The tissue-intrinsic local microenvironment makes a decisive influence on tumor invasiveness (2019)
  • Author(s): Rei Kobayashi, Yasuyuki Fujita, Yoichiro Tamori
  • Organizer: Barcelona BioMed Conference
  • Int'l Joint Research / Invited
• [Presentation] Decisive roles of the tissue-intrinsic local microenvironment in tumor evolution (2019)
  • Author(s): Yoichiro Tamori
  • Organizer: The 4th Morphomeostasis Meeting
  • Invited
• [Presentation] The tissue-intrinsic local microenvironment makes a decisive influence on tumor invasiveness (2019)
  • Author(s): Rei Kobayashi, Yasuyuki Fujita, Yoichiro Tamori
  • Organizer: 60th Annual Drosophila Research Conference
  • Int'l Joint Research
• [Presentation] 腫瘍の浸潤性を左右する上皮内在性微小環境の解析 (2019)
  • Author(s): 小林怜, 藤田恭之、田守洋一郎
  • Organizer: 細胞競合コロキウム