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Elucidation of circulating cluster niche for hematogenous metastasis

Research Project

Project/Area Number 21K19535
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
Research InstitutionKumamoto University

Principal Investigator

Ishimoto Takatsugu  熊本大学, 病院, 特任准教授 (00594889)

Co-Investigator(Kenkyū-buntansha) 中島 雄太  熊本大学, 大学院先端科学研究部(工), 准教授 (70574341)
北村 裕介  熊本大学, 大学院先端科学研究部(工), 助教 (80433019)
Project Period (FY) 2021-07-09 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2022: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2021: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Keywords血行性がん転移 / CTCs / 血小板 / 線維芽細胞 / 腫瘍循環細胞 / CAFs / CTCクラスター / 血行性転移 / ニッチ
Outline of Research at the Start

がん細胞が血行性に転移するプロセスにおいて循環腫瘍細胞(Circulating Tumor Cells: CTCs)は血小板・マクロファージなどの非がん細胞とクラスターを形成し、ホストの免疫や様々なストレスを回避していることが示唆されているが、CTCsを包み込むクラスターニッチの本質的意義は明らかになっていない。本研究では、独自に開発したアプタマー修飾フィルターと、共同研究により新たに樹立したマウス胃がん細胞(DT-p53KO-KRASm-IB-LUC)の肝転移モデルを用いて、循環血液中のCTCクラスターニッチの全貌を明らかにすることを目指す

Outline of Final Research Achievements

The purpose of this study was to clarify the significance of circulating tumor cells (CTCs) forming clusters with non-cancer cells such as platelets, macrophages, and fibroblasts. Clusters of cancer and non-cancer cells were detected in the blood of gastric cancer patients with distant metastasis and in a mouse model of hematogenous cancer metastasis. We demonstrated that disruption of the clusters with anti-platelet antibodies significantly suppressed hematogenous metastasis. Moreover, using in vivo imaging techniques, we captured CTC clusters circulating in blood vessels and showed their presence.

Academic Significance and Societal Importance of the Research Achievements

血行性がん転移に関する研究は長年にわたり行われてきたが、未だ転移を制御するまでに至っていない。本研究によって循環腫瘍細胞(CTCs)クラスターの形成が血行性転移形成に重要な意義を有していることが明らかになり、血行性転移や再発のバイオマーカーとしての循環腫瘍細胞(CTCs)検出に留まらず、がん細胞の生存をサポートするCTCクラスターを制御することで再発・転移を抑制する革新的な治療法開発に繋がることが期待できる。

Report

(3 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • Research Products

    (20 results)

All 2023 2022 2021 Other

All Int'l Joint Research (3 results) Journal Article (11 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 11 results,  Open Access: 9 results) Presentation (6 results) (of which Int'l Joint Research: 2 results,  Invited: 3 results)

  • [Int'l Joint Research] Duke-NUS Medical School(シンガポール)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Duke-NUS Medical School(シンガポール)

    • Related Report
      2021 Research-status Report
  • [Int'l Joint Research] MD-Anderson Cancer Center(米国)

    • Related Report
      2021 Research-status Report
  • [Journal Article] A novel tdTomato transgenic mouse model to visualize FAP‐positive cancer‐associated fibroblasts2023

    • Author(s)
      Wei F , Uchihara T , Yonemura A , Yasuda-Yoshihara N , Yasuda T , Semba T , Fukuda M , Akiyama T , Kitamura F , Kariya R , Yamasaki J , Aihara K , Yamashita K , Nagano O , Okada S , Baba H , Ishimoto T
    • Journal Title

      The FEBS Journal

      Volume: - Issue: 10 Pages: 2604-2615

    • DOI

      10.1111/febs.16712

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Stromal reprogramming through dual PDGFRα/β blockade boosts the efficacy of anti-PD-1 immunotherapy in fibrotic tumors.2022

    • Author(s)
      T. Akiyama, T. Yasuda, T. Uchihara, N. Yasuda-Yoshihara, BJY. Tan, A. Yonemura, T. Semba, J. Yamasaki, Y. Komohara, K. Ohnishi, F. Wei, L. Fu, J. Zhang, F. Kitamura, K. Yamashita, K. Eto, S. Iwagami, H. Tsukamoto, T. Umemoto, M. Masuda, O. Nagano, Y. Satou, H. Saya, P. Tan, H. Baba, T. Ishimoto
    • Journal Title

      Cancer Res.

      Volume: 83 Issue: 5 Pages: 753-770

    • DOI

      10.1158/0008-5472.can-22-1890

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Tumor microenvironmental 15‐PGDH depletion promotes fibrotic tumor formation and angiogenesis in pancreatic cancer2022

    • Author(s)
      Bu L, Yonemura A, Yasuda-Yoshihara N, Uchihara T, Ismagulov G, Takasugi S, Yasuda T, Okamoto Y, Kitamura F, Akiyama T, Arima K, Itoyama R, Zhang J, Fu L, Hu X, Wei, F, Arima Y, Moroishi T, Nishiyama K, Sheng G, Mukunoki T, Otani J, Baba H, Ishimoto T
    • Journal Title

      Cancer Science

      Volume: 113 Issue: 10 Pages: 3579-3592

    • DOI

      10.1111/cas.15495

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Intracellular MUC20 variant 2 maintains mitochondrial calcium homeostasis and enhances drug resistance in gastric cancer2022

    • Author(s)
      Fu Lingfeng、Yonemura Atsuko、Yasuda-Yoshihara Noriko、Umemoto Terumasa、Zhang Jun、Yasuda Tadahito、Uchihara Tomoyuki、Akiyama Takahiko、Kitamura Fumimasa、Yamashita Kohei、Okamoto Yuya、Bu Luke、Wei Feng、Hu Xichen、Liu Yang、Ajani Jaffer A.、Tan Patrick、Baba Hideo、Ishimoto Takatsugu
    • Journal Title

      Gastric Cancer

      Volume: 25 Issue: 3 Pages: 542-557

    • DOI

      10.1007/s10120-022-01283-z

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Single-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric Cancer2022

    • Author(s)
      Kumar V, Ramnarayanan K, Sundar R, Padmanbahan N, Srivastava S, Koiwa M, Yasuda T, Koh V, Huang K, Tay S, Ho S, Tan A, Ishimoto T
    • Journal Title

      Cancer Discovery

      Volume: 12 Issue: 3 Pages: 670-691

    • DOI

      10.1158/2159-8290.cd-21-0683

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] MEK inhibition suppresses metastatic progression of <i>KRAS</i> ‐mutated gastric cancer2022

    • Author(s)
      Yamasaki Juntaro、Hirata Yuki、Otsuki Yuji、Suina Kentaro、Saito Yoshiyuki、Masuda Kenta、Okazaki Shogo、Ishimoto Takatsugu、Saya Hideyuki、Nagano Osamu
    • Journal Title

      Cancer Science

      Volume: 113 Issue: 3 Pages: 916-925

    • DOI

      10.1111/cas.15244

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Metabolic shift to serine biosynthesis through 3-PG accumulation and PHGDH induction promotes tumor growth in pancreatic cancer2021

    • Author(s)
      Itoyama R, Yasuda-Yoshihara N, Kitamura F, Yasuda T, Bu L, Yonemura A, Uchihara T, Arima K, Hu X, Jun Z, Okamoto Y, Akiyama T, Yamashita K, Nakao Y, Yusa T, Kitano Y, Higashi T, Miyata T, Imai K, Hayashi H, Yamashita Y, Mikawa T, Kondoh H, Baba H, Ishimoto T
    • Journal Title

      Cancer Letters

      Volume: 523 Pages: 29-42

    • DOI

      10.1016/j.canlet.2021.09.007

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Assessment of the Diagnostic Efficiency of a Liquid Biopsy Assay for Early Detection of Gastric Cancer2021

    • Author(s)
      Izumi D, Zhu Z, Chen Y, Toden S, Huo X, Kanda M, Ishimoto T, Gu D, Tan M, Kodera Y, Baba H, Li W, Chen J, Wang X, Goel A
    • Journal Title

      JAMA Network Open

      Volume: 4 Issue: 8 Pages: 2121129-2121129

    • DOI

      10.1001/jamanetworkopen.2021.21129

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Protocol to establish cancer-associated fibroblasts from surgically resected tissues and generate senescent fibroblasts2021

    • Author(s)
      Yasuda T, Koiwa M, Yonemura A, Akiyama T, Baba H, Ishimoto T
    • Journal Title

      STAR Protocols

      Volume: 2 Issue: 2 Pages: 100553-100553

    • DOI

      10.1016/j.xpro.2021.100553

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination2021

    • Author(s)
      Yasuda T, Koiwa M, Yonemura A, Miyake K, Kariya R, Kubota S, Yokomizo-Nakano T, Yasuda-Yoshihara N, Uchihara T, Itoyama R, Bu L, Fu L, Arima K, Izumi D, Iwagami S, Eto K, Iwatsuki M, Baba Y, Yoshida N, Ohguchi H, Okada S, Matsusaki K, Sashida G, Takahashi A, Tan P, Baba H, Ishimoto T.
    • Journal Title

      Cell Reports

      Volume: 34 Issue: 8 Pages: 108779-108779

    • DOI

      10.1016/j.celrep.2021.108779

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Conflicting metabolic alterations in cancer stem cells and regulation by the stromal niche2021

    • Author(s)
      Yasuda T, I Ishimoto T, Baba H
    • Journal Title

      Regenerative Therapy

      Volume: 17 Pages: 8-12

    • DOI

      10.1016/j.reth.2021.01.005

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Single-cell proteomic profiling of malignant ascites in gastric cancer reveals the microenvironment promoting peritoneal dissemination2023

    • Author(s)
      Takatsugu Ishimoto
    • Organizer
      JSPS Core-to-Core Program A. Mini-Symposium 「Applications of mass cytometry in basic and clinical research」
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Single-cell proteomic profiling of malignant ascites in gastric cancer reveals the microenvironment promoting peritoneal dissemination2022

    • Author(s)
      Takatsugu Ishimoto
    • Organizer
      第45回日本分子生物学会年会、フォーラム2F-07 「個体レベルの生命科学の創発」
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] PDGFR阻害によるスキルス胃癌間質リプログラミングを介した複合がん免疫療法2022

    • Author(s)
      石本 崇胤
    • Organizer
      第33回日本消化器癌発生学会総会 シンポジウム1「免疫を考慮した消化器癌研究」
    • Related Report
      2022 Annual Research Report
  • [Presentation] スキルス胃癌免疫微小環境リモデリングによる治療戦略2022

    • Author(s)
      石本 崇胤
    • Organizer
      第93回日本胃癌学会総会、ワークショップ6「胃癌における微小環境の分子機序の解明と臨床的意義
    • Related Report
      2021 Research-status Report
  • [Presentation] 複合がん免疫療法に向けたスキルス胃癌間質リプログラミング分子基盤の解明2021

    • Author(s)
      石本 崇胤
    • Organizer
      第29回JDDW 2021シンポジウム8「がん微小環境を標的とした消化器がん治療の新展望」
    • Related Report
      2021 Research-status Report
  • [Presentation] Extracellular vesicles from cancer-associated fibroblasts induce drug resistance.2021

    • Author(s)
      Takatsugu Ishimoto
    • Organizer
      34th Workshop of the European Helicobacter and Microbiota Study Group
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research / Invited

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Published: 2021-07-13   Modified: 2024-01-30  

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