Elucidation of circulating cluster niche for hematogenous metastasis

• Project/Area Number: 21K19535
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Kumamoto 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: ¥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。

Research Products

• [Int'l Joint Research] Duke-NUS Medical School(シンガポール)
• [Int'l Joint Research] Duke-NUS Medical School(シンガポール)
• [Int'l Joint Research] MD-Anderson Cancer Center(米国)
• [Journal Article] A novel tdTomato transgenic mouse model to visualize FAP‐positive cancer‐associated fibroblasts (2023)
  • 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
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tumor microenvironmental 15‐PGDH depletion promotes fibrotic tumor formation and angiogenesis in pancreatic cancer (2022)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intracellular MUC20 variant 2 maintains mitochondrial calcium homeostasis and enhances drug resistance in gastric cancer (2022)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Single-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric Cancer (2022)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] MEK inhibition suppresses metastatic progression of <i>KRAS</i> ‐mutated gastric cancer (2022)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic shift to serine biosynthesis through 3-PG accumulation and PHGDH induction promotes tumor growth in pancreatic cancer (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of the Diagnostic Efficiency of a Liquid Biopsy Assay for Early Detection of Gastric Cancer (2021)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protocol to establish cancer-associated fibroblasts from surgically resected tissues and generate senescent fibroblasts (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination (2021)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Conflicting metabolic alterations in cancer stem cells and regulation by the stromal niche (2021)
  • 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
  • Peer Reviewed / Open Access
• [Presentation] Single-cell proteomic profiling of malignant ascites in gastric cancer reveals the microenvironment promoting peritoneal dissemination (2023)
  • Author(s): Takatsugu Ishimoto
  • Organizer: JSPS Core-to-Core Program A. Mini-Symposium 「Applications of mass cytometry in basic and clinical research」
  • Int'l Joint Research / Invited
• [Presentation] Single-cell proteomic profiling of malignant ascites in gastric cancer reveals the microenvironment promoting peritoneal dissemination (2022)
  • 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」
  • 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」
• [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
• [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」
• [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
  • Int'l Joint Research / Invited