Tumor microenvironment for metastasis and drug resistance proved by advanced macrocyclic peptide technology

• Project/Area Number: 19H03499
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kanazawa University
• Principal Investigator: MATSUMOTO KUNIO 金沢大学, がん進展制御研究所, 教授 (90201780)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2021: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2020: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2019: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: がん転移 / がん微小環境 / 環状ペプチド / 細胞増殖因子 / 分子イメージング / 増殖因子受容体 / HGF / MET / 転移 / 薬剤耐性 / チロシンキナーゼ / 高速原子間力顕微鏡 / 増殖因子

Outline of Research at the Start

増殖因子活性分子種の特異的検出・阻害はがん微小環境形成機構の理解に必須である。私たちはMET/HGF受容体に高親和性結合する環状ペプチド、活性型HGF（tcHGF）にのみ特異的に結合・阻害する環状ペプチドそれぞれを取得した。本研究は、環状ペプチド化学と連携し、HGFの活性化機構の解明、がん転移ニッチ形成におけるtcHGFの機能、MET活性化がん細胞の検出を検証する。環状ペプチドは抗体に匹敵する高い標的特異性をもつことに加え、分子修飾の容易さ、小さい分子サイズなど優位性をもつ。がん転移や薬剤耐性をもたらすがん微小環境の新しい理解、診断・治療の基礎技術の確立を環状ペプチドとの融合研究により進める。

Outline of Final Research Achievements

Because activation of the HGF-MET receptor signal is involved in cancer metastasis and drug resistance, specific detection and inhibition of HGF leads to cancer diagnosis and treatment. We have obtained the cyclic peptide HiP-8, which inhibits HGF with excellent affinity and specificity. HiP-8 showed excellent performance as a molecule tool for PET imaging diagnosis. Using a lung metastasis model, we clarified the mechanism of cancer metastasis microenvironment formation mediated by MET activation. In metastatic model, HiP-8 inhibited cancer metastasis. Cyclic peptide-based molecular technology with high target specificity is expected to bring progress in cancer diagnosis and therapeutics.

Academic Significance and Societal Importance of the Research Achievements

環状ペプチドをファルマコフォアとして、抗体並みの高い標的特異性もつ高性能創薬候補分子を創成できる。本研究ではHGFに対して高い特異性で結合し、同時にHGFを阻害する環状ペプチド（HiP-8）を取得することに成功した。また、標識HiP-8分子を検出用分子として、ヒトがん移植マウスモデルでPET診断を実施し、HiP-8はPET診断用分子として高い性能をもつことを検証した。HGF-MET受容体系を含め、細胞増殖因子受容体の活性化は、発がん、がん転移や薬剤耐性に代表される治療抵抗性に関与する。本研究で取得された分子・技術は、細胞増殖因子・受容体活性化の特異検出のための診断・治療につながると期待される。

Research Products

• [Journal Article] SRC kinase activator CDCP1 promotes hepatocyte growth factor-induced cell migration/invasion of a subset of breast cancer cells (2022)
  • Author(s): Kawase Naoyuki、Sugihara Atsuya、Kajiwara Kentaro、Hiroshima Michio、Akamatsu Kanako、Nada Shigeyuki、Matsumoto Kunio、Ueda Masahiro、Okada Masato
  • Journal Title: Journal of Biological Chemistry Volume: 298 Issue: 3 Pages: 101630-101630
  • DOI: 10.1016/j.jbc.2022.101630
  • Peer Reviewed / Open Access
• [Journal Article] Dual blockade of MET and VEGFR2 signaling pathways as a potential therapeutic maneuver for peritoneal carcinomatosis in scirrhous gastric cancer. (2022)
  • Author(s): Kasai S, Kuwayama N, Motoo Y, Kawashima A, Matsumoto K, Yano S, Matsushima K, Yasumoto K.
  • Journal Title: Biochem Biophys Res Commun Volume: 600 Pages: 80-86
  • DOI: 10.1016/j.bbrc.2022.02.045
  • Peer Reviewed / Open Access
• [Journal Article] N-glycosylation regulates MET processing and signaling (2022)
  • Author(s): Atsushi Saitou, Yoshihiro Hasegawa, Naoki Fujitani, Shigeru Ariki, Yasuaki Uehara, Ukichiro Hashimoto, Atsushi Saito, Koji Kuronuma, Kunio Matsumoto, Hirofumi Chiba, Motoko Takahashi
  • Journal Title: Cancer Science Volume: ー Issue: 4 Pages: 1292-1304
  • DOI: 10.1111/cas.15278
  • Peer Reviewed / Open Access
• [Journal Article] Placental leucine aminopeptidase as a potential specific urine biomarker for invasive ovarian cancer. (2022)
  • Author(s): Matsukawa T, Mizutani S, Matsumoto K, Kato Y, Yoshihara M, Kajiyama H, Shibata K.
  • Journal Title: J Clin Med Volume: 11 Issue: 1 Pages: 222-222
  • DOI: 10.3390/jcm11010222
  • Peer Reviewed / Open Access
• [Journal Article] Lasso-grafting of macrocyclic peptide pharmacophores yields multi-functional proteins (2021)
  • Author(s): Mihara E, Watanabe S, Bashiruddin N, Nakamura N, Matoba K, Maini R, Yin Y, Sakai K, Arimori T, Matsumoto K, Suga H, and Takagi J.
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 1543-1543
  • DOI: 10.1038/s41467-021-21875-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CDCP1 promotes compensatory renal growth by integrating Src and Met signaling (2021)
  • Author(s): Kajiwara Kentaro、Yamano Shotaro、Aoki Kazuhiro、Okuzaki Daisuke、Matsumoto Kunio、Okada Masato
  • Journal Title: Life Science Alliance Volume: 4 Issue: 4 Pages: 202000832-202000832
  • DOI: 10.26508/lsa.202000832
  • Peer Reviewed / Open Access
• [Journal Article] Dimer interface in natural variant NK1 is dispensable for HGF-dependent Met receptor activation. (2021)
  • Author(s): Tahira Y, Sakai K, Sato H, Imamura R, Matsumoto K.
  • Journal Title: Int J Mol Sci Volume: 22 Pages: 9240-9240
  • Peer Reviewed
• [Journal Article] De novo peptide grafting to a self-assembling nanocapsule yields a hepatocyte growth factor receptor agonist (2021)
  • Author(s): Komatsu Yamato、Terasaka Naohiro、Sakai Katsuya、Mihara Emiko、Wakabayashi Risa、Matsumoto Kunio、Hilvert Donald、Takagi Junichi、Suga Hiroaki
  • Journal Title: iScience Volume: 24 Issue: 11 Pages: 103302-103302
  • DOI: 10.1016/j.isci.2021.103302
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Macrocyclic Peptide-Conjugated Tip for Fast and Selective Molecular Recognition Imaging by High-Speed Atomic Force Microscopy (2021)
  • Author(s): L. Pupplin, D. Kanayama, N. Terasaka, K. Sakai, N. Kodera, K. Umeda, A. Sumino, M. Arin, W. Wei, H. Tanaka, T. Fukuma, H. Suga, K. Matsumoto, M. Shibata
  • Journal Title: ACS Applied Materials & Interfaces Volume: 13(46) Issue: 46 Pages: 54817-54829
  • DOI: 10.1021/acsami.1c17708
  • Peer Reviewed / Open Access
• [Journal Article] The constitutive high affinity Met binding site in the kringle domain is dispensable for the signaling activity of hepatocyte growth factor. (2020)
  • Author(s): Umitsu M, Sakai K, Tamura-Kawakami K, Matsumoto K, Takagi J.
  • Journal Title: JOURNAL OF BIOCHEMISTRY Volume: - Issue: 6 Pages: 577-586
  • DOI: 10.1093/jb/mvaa006
  • NAID: 40022260383
  • Peer Reviewed / Open Access
• [Journal Article] Proteasomal degradation of polycomb-group protein CBX6 confers MMP-2 expression essential for mesothelioma invasion (2020)
  • Author(s): Sakai Katsuya、Nishiuchi Takumi、Tange Shoichiro、Suzuki Yoshinori、Yano Seiji、Terashima Minoru、Suzuki Takeshi、Matsumoto Kunio
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 16678-16678
  • DOI: 10.1038/s41598-020-72448-y
  • Peer Reviewed / Open Access
• [Journal Article] Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer (2020)
  • Author(s): Wang Rong、Yamada Tadaaki、Kita Kenji、Taniguchi Hirokazu、Arai Sachiko、Fukuda Koji、Terashima Minoru、Ishimura Akihiko、Nishiyama Akihiro、Tanimoto Azusa、Takeuchi Shinji、Ohtsubo Koshiro、Wang Wei、Suzuki Takeshi、Yano Seiji et. al.
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 4607-4607
  • DOI: 10.1038/s41467-020-18442-4
  • NAID: 120007186801
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cyclic Peptide-Based Biologics Regulating HGF-MET. (2020)
  • Author(s): Hiroki Sato, Ryu Imamura, Hiroaki Suga, Kunio Matsumoto, Katsuya Sakai
  • Journal Title: International journal of molecular sciences Volume: 21 Issue: 21 Pages: 7977-7977
  • DOI: 10.3390/ijms21217977
  • Peer Reviewed / Open Access
• [Journal Article] New insights into human endometrial aminopeptidases in both implantation and menstruation (2019)
  • Author(s): Mizutani S, Matsumoto K, Kato Y, Mizutani E, Mizutani H, Iwase A, Shibata K.
  • Journal Title: Biochim Biophys Acta - Proteins & Proteomics Volume: 1868 Issue: 2 Pages: 140332-140332
  • DOI: 10.1016/j.bbapap.2019.140332
  • Peer Reviewed / Open Access
• [Journal Article] Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor. (2019)
  • Author(s): Sakai K, Passioura T, Sato H, Ito K, Furuhashi H, Umitsu M, Takagi J, Kato Y, Mukai H, Warashina S, Zouda M, Watanabe Y, Yano S, Shibata M, Suga H, Matsumoto K
  • Journal Title: Nature Chemical Biology Volume: 15 Issue: 6 Pages: 598-606
  • DOI: 10.1038/s41589-019-0285-7
  • Peer Reviewed / Open Access
• [Journal Article] Distinct Localization of Mature HGF from its Precursor Form in Developing and Repairing the Stomach. (2019)
  • Author(s): Jangphattananont N, Sato H, Imamura R, Sakai K, Terakado Y, Murakami K, Barker N, Oshima H, Oshima M, Takagi J, Kato Y, Yano S, Matsumoto K
  • Journal Title: International Journal of Molecular Sciences Volume: 12 Issue: 12 Pages: 2955-2955
  • DOI: 10.3390/ijms20122955
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impaired ligand-dependent MET activation caused by an extracellular SEMA domain missense mutation in lung cancer. (2019)
  • Author(s): Miao W, Sakai K, Sato H, Imamura R, Jangphattananont N, Takagi J, Nishita M, Minami Y, Matsumoto K
  • Journal Title: Cancer Science Volume: 110 Issue: 10 Pages: 3340-3349
  • DOI: 10.1111/cas.14142
  • NAID: 120006733132
  • Peer Reviewed / Open Access
• [Presentation] HGF-MET系を制御する環状ペプチドの特性と応用. (2022)
  • Author(s): 松本邦夫.
  • Organizer: 第17回 日本分子標的治療学会TRワークショップ
  • Invited
• [Presentation] HGF-MET系を標的に新展開する環状ペプチド革新創薬. (2022)
  • Author(s): 松本邦夫.
  • Organizer: 第23回 北陸COG Open Clinical Conference
  • Invited
• [Presentation] 腫瘍局所でのHGF活性化を捉える環状ペプチドPETプローブの開発. (2021)
  • Author(s): 藁科翔太，佐藤拓輝，造田真希，酒井克也，Toby Passioura，和田康弘，菅裕明，松本邦夫，渡辺恭良，向井英史.
  • Organizer: 第15回 日本分子イメージング学会 総会・学術集会
• [Presentation] HGF conversion in bronchial epithelial cells triggers pre-metastatic niche formation in the lung. (2021)
  • Author(s): Hiroki Sato, Katsuya Sakai, Ryu Imamura, Kunio Matsumoto.
  • Organizer: 第80回日本癌学会総会
• [Presentation] 集団遊走における細胞の機械的拘束依存的な増殖因子シグナル活性動態変化による先導細胞の運命決定. (2021)
  • Author(s): 日野直也，松田樹生也，真流玄武，酒井克也，今村龍，青木一洋，寺井健太，平島剛志，松本邦夫，松田道行.
  • Organizer: 第73回日本細胞生物学会大会
• [Presentation] 腎臓の代償性肥大におけるSrcシグナルの時空間的制御. (2021)
  • Author(s): 梶原健太郎，山野荘太郎，青木一洋，奥崎大介，松本邦夫，岡田雅人.
  • Organizer: 第73回日本細胞生物学会大会
• [Presentation] METの糖鎖による機能制御メカニズムの解析. (2021)
  • Author(s): 齋藤淳，長谷川喜弘，藤谷直樹，有木茂，上原康昭，松本邦夫，高橋素子.
  • Organizer: 第94回日本生化学大会
• [Presentation] ヒトaminopeptidase A組換えタンパク質の臓器分布および胎児移行の解析. (2021)
  • Author(s): 津本彩乃，増尾友佑，近藤友美，今村龍，水谷栄彦，松本邦夫，加藤将夫.
  • Organizer: 日本薬物動態学会 第36回年会
• [Presentation] 高速AFMを起点に観える増殖因子受容体METの動的活性化と創薬. (2021)
  • Author(s): 松本邦夫.
  • Organizer: CBI学会 第419回研究講演会
  • Invited
• [Presentation] "高速AFM で観る"がん関連分子と応用. (2021)
  • Author(s): 松本邦夫.
  • Organizer: 【ナノプローブテクノロジー第167 委員会】 第98 回研究会
  • Invited
• [Presentation] バイオベンチャーの意義と産学連携の創薬開発に向き合う姿勢． (2021)
  • Author(s): 松本邦夫.
  • Organizer: シンポジウム「新薬開発に向けた産学連携の問題点と将来展望」，第80回日本癌学会総会
  • Invited
• [Presentation] 胃組織修復および発がん機構における活性型HGFの役割. (2020)
  • Author(s): 佐藤拓輝，酒井克也，今村龍，大島浩子，大島正伸，村上和弘，寺門侑美，加藤幸成，矢野聖二，松本邦夫．
  • Organizer: 第79回日本癌学会総会
• [Presentation] 肺癌患者より同定されたHGF受容体Metにおけるミスセンス変異体（V370D）の解析. (2020)
  • Author(s): 今村龍，酒井克也，佐藤拓輝，松本邦夫．
  • Organizer: 第79回日本癌学会総会
• [Presentation] 肺腺がん細胞上のc-Met受容体分子を原子間力顕微鏡で観察する方法の開発. (2020)
  • Author(s): 市川壮彦, 佐藤拓輝, 松本邦夫, 福間剛士.
  • Organizer: 第72回 日本細胞生物学会大会
• [Presentation] MET受容体の人為制御と構造基盤. (2020)
  • Author(s): 酒井克也，高木淳一，菅裕明，柴田幹大，松本邦夫.
  • Organizer: 第93回日本生化学会大会
  • Invited
• [Presentation] Cyclic Peptide-based Drug Discovery Regulating HGF-MET. (2020)
  • Author(s): Kunio Matsumoto
  • Organizer: 第63回日本糖尿病学会年次学術集会シンポジウム “肝細胞の生物学 Up to Date”
• [Presentation] 組換えタンパク質医薬が私たちにもたらしたものとこれから． (2020)
  • Author(s): 松本邦夫.
  • Organizer: 第65回 日本生殖医療学会学術講演会・総会ランチョンセミナー3
• [Presentation] ダイナミックな運動性をもつマルチドメイン蛋白質HGFの高難度結晶化の試み. (2019)
  • Author(s): 中村希，岩佐奈実，川上紗代子，有森貴夫，酒井克也，松本邦夫，高木淳一．
  • Organizer: 第19回日本蛋白質科学会年会
• [Presentation] 環状ペプチドによるHGF阻害と高速原子間力顕微鏡による分子動態計測. (2019)
  • Author(s): 酒井克也，佐藤拓輝，柴田幹大，高木淳一，加藤幸成，向井英司，渡辺恭良，矢野聖二，菅裕明，松本邦夫.
  • Organizer: 第92回日本生化学会大会
  • Invited
• [Presentation] Specific detection of active HGF for diagnosis reflecting activation status of HGF-MET signaling by macrocyclic peptide. (2019)
  • Author(s): Sato H, Sakai K, Passioura T, Imamura R, Mukai H, Watanabe Y, Yano S, Suga H, Matsumoto K.
  • Organizer: 第78回日本癌学会総会
• [Presentation] Wnt5a-Ror1 signaling promotes invasion of lung adenocarcinoma cells through Rif-mediated formation of filopodia. (2019)
  • Author(s): Nishita M, Matsumoto K, Minami Y.
  • Organizer: 第78回日本癌学会総会
• [Presentation] Mature-form hepatocyte growth factor-specific PET imaging in tumor-bearing mice using a macrocyclic peptide probe. (2019)
  • Author(s): Mukai H, Warashina S, Sato H, Zouda M, Sakai K, Passioura T, Wada Y, Suga H, Matsumoto K, Watanabe Y.
  • Organizer: World Molecular Imaging Congress
  • Int'l Joint Research
• [Presentation] Ror1 signaling through Dvl and Rif promotes invasion of lung adenocarcinoma cells. (2019)
  • Author(s): Nishita M, Kamizaki K, Nishikaku I, Shibuya H, Matsumoto M, Minami Y.
  • Organizer: American Society of Cell Biology
  • Int'l Joint Research
• [Presentation] 細胞外SEMAドメインミスセンス変異に起因するリガンド依存性MET活性化の障害. (2019)
  • Author(s): Tahira Y, Miao W, Sakai K, Sato H, Imamura R, Jangphattananont N, Matsumoto K.
  • Organizer: 第42回 日本分子生物学会年会
• [Presentation] Distinct localization of mature HGF and precursor form in developing and repairing stomach. (2019)
  • Author(s): Jangphattananont N, Sato H, Imamura R, Sakai K, Terakado Y, Murakami K, Barker N, Oshima H, Oshima M, Takagi J, Kato Y, Matsumoto K.
  • Organizer: 第42回 日本分子生物学会年会
• [Presentation] Macrocyclic Peptides Targeting HGF-MET (2019)
  • Author(s): Matsumoto K.
  • Organizer: 3rd NanoLSI Symposium
  • Int'l Joint Research
• [Presentation] 環状ペプチド技術と細胞増殖因子研究融合による合成バイオロジクス. (2019)
  • Author(s): 松本邦夫.
  • Organizer: 薬物動態懇話会 第42回年会
  • Invited
• [Book] ペプチド創薬の最前線 (2019)
  • Author(s): 佐藤拓輝，酒井克也，菅裕明，松本邦夫（分担執筆）
  • Total Pages: 265
  • Publisher: シーエムシー出版
  • ISBN: 9784781314174
• [Remarks] Researcher’s Voice #1: 分野融合研究でHGFを紐解きがん研究を深める
  • URL: https://www.kanazawa-u.ac.jp/research/re-voice/rv1
• [Remarks] がんの診断・治療につながる環状ペプチドを発見！
  • URL: https://nanolsi.kanazawa-u.ac.jp/post-6718/
• [Remarks] 10億分の1mの世界！生命科学者は「踊るタンパク質」の夢を見るか
  • URL: https://gendai.ismedia.jp/articles/-/70128
• [Remarks] Nature Index
  • URL: https://www.natureindex.com/article/10.1038/s41589-019-0285-7