Development of anti-stromal therapeutic strategy based on histological molecular subtyping of gastric cancer stroma.

• Project/Area Number: 20H03531
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Kumamoto University
• Principal Investigator: Ishimoto Takatsugu 熊本大学, 病院, 特任准教授 (00594889)
• Co-Investigator(Kenkyū-buntansha): 岩槻 政晃 熊本大学, 大学院生命科学研究部(医), 助教 (50452777) ; 須田 年生 熊本大学, 国際先端医学研究機構, 卓越教授 (60118453)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: 腫瘍微小環境 / 胃癌 / CAFs / 多様性 / 抗PD-1抗体 / ストローマ / 胃がん / 細胞老化 / 細胞外小胞

Outline of Research at the Start

固形癌は癌細胞だけでなく腫瘍間質（ストローマ）に多様な細胞分画を含んでおり、奏効率の高い薬物療法を開発するためには、異なる細胞分画間での相互作用を理解することが重要である。なかでもCAFs (Cancer-Associated Fibroblasts)が癌の進展や浸潤・転移を促進していることは世界中の研究者により立証されている。本研究計画では、びまん性・腸型胃癌組織から樹立したCAFsバイオバンクを用いたシングルセル解析（RNAシーケンシング・プロテオミクス）により、組織型別の胃癌間質分子サブタイピングをおこない、癌進展や薬剤抵抗性獲得を制御する新規治療ターゲットを創出することを目的とする。

Outline of Final Research Achievements

We focused on cancer-associated fibroblasts (CAFs) among the various cell types that form cancer tissue, and applied single-cell analysis to CAFs with the aim of developing new therapeutic targets for tumor stroma. In current study, we found that extracellular vesicles derived from CAFs and cytokines such as IL-6 act on cancer cells to promote cancer progression and metastasis, and demonstrated that there are three subgroups of CAFs in the gastric cancer stroma and identified the specific subgroup suppresses immunity against cancer.

Academic Significance and Societal Importance of the Research Achievements

癌は組織として存在し、多様な細胞群で構成されている。さらに各細胞群の中にもサブグループが存在し、各グループがネットワークを形成していることが明らかになった。今後の癌治療を考える際には、このネットワークを遮断した上で効率良く癌細胞を標的とした治療を行うことが重要となる。特にスキルス胃癌のような線維化が強い癌種では、Cancer associated fibroblasts (CAFs)と呼ばれる線維芽細胞が癌を促進する腫瘍間質で重要な働きをしており、治療ターゲットとなり得ることを明らかにした。

Research Products

• [Int'l Joint Research] Duke-NUS Medical School(シンガポール)
• [Int'l Joint Research] MD-Anderson Cancer Center(米国)
• [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] 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] Gut microbiome in gastrointestinal cancer: a friend or foe? (2022)
  • Author(s): Liu Y, Baba Y, Ishimoto T, Gu X, Zhang J, Nomoto D, Okadome K, Baba H, Qiu P
  • Journal Title: International Journal of Biological Sciences Volume: 18 Issue: 10 Pages: 4101-4117
  • DOI: 10.7150/ijbs.69331
  • 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] The Gut Microbiota in Inflammatory Bowel Disease (2022)
  • Author(s): Qiu P, Ishimoto T, Fu L, Zhang J, Zhang Z, Liu Y
  • Journal Title: Frontiers in Cellular and Infection Microbiology Volume: 12
  • DOI: 10.3389/fcimb.2022.733992
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Journal Article] Extracellular Vesicles from Cancer-Associated Fibroblasts Containing Annexin A6 Induces FAK-YAP Activation by Stabilizing β1 Integrin, Enhancing Drug Resistance (2020)
  • Author(s): Uchihara T, Miyake K, Yonemura A, Komohara Y, Itoyama R, Koiwa M, Yasuda T, Arima K, Harada K, Eto K, Hayashi H, Iwatsuki M, Iwagami S, Baba Y, Yoshida N, Yashiro M, Masuda M, Ajani Jaffer A, Tan Patrick, Baba H, Ishimoto T
  • Journal Title: Cancer Research Volume: 80 Issue: 16 Pages: 3222-3235
  • DOI: 10.1158/0008-5472.can-19-3803
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional diversity of cancer‐associated fibroblasts in modulating drug resistance (2020)
  • Author(s): Bu Luke、Baba Hideo、Yasuda Tadahito、Uchihara Tomoyuki、Ishimoto Takatsugu
  • Journal Title: Cancer Science Volume: 111 Issue: 10 Pages: 3468-3477
  • DOI: 10.1111/cas.14578
  • Peer Reviewed / Open Access
• [Journal Article] Gastric Cancer Stem Cells: Current Insights into the Immune Microenvironment and Therapeutic Targets (2020)
  • Author(s): Fu L, Bu L, Yasuda T, Koiwa M, Akiyama T, Uchihara T, Baba H, Ishimoto T
  • Journal Title: Biomedicines Volume: 8 Issue: 1 Pages: 7-7
  • DOI: 10.3390/biomedicines8010007
  • 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 AMini-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
• [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
• [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] 34th Workshop of the European Helicobacter and Microbiota Study Group (2021)
  • Author(s): Takatsugu Ishimoto
  • Organizer: Extracellular vesicles from cancer-associated fibroblasts induce drug resistance.
  • Int'l Joint Research / Invited
• [Presentation] Elucidation of immune microenvironment and therapeutic target in scirrhous gastric cancer strorma. (2021)
  • Author(s): Takatsugu Ishimoto
  • Organizer: 第93回日本胃癌学会総会 会長特別企画2スキルス胃癌研究のこれまでとこれから
  • Invited
• [Presentation] 胃がん間質ダイバーシティの解明と治療標的の創出 (2020)
  • Author(s): 石本 崇胤
  • Organizer: 第31回日本消化器癌発生学会総会 田原榮一賞受賞講演
  • Invited
• [Presentation] 腹膜播種形成を促進するがん性腹水中老化細胞の意義 (2020)
  • Author(s): 石本 崇胤
  • Organizer: 第20回抗加齢医学会総会シンポジウム3「DNA損傷応答と老化の表現型」
  • Invited