膵臓がんの線維化と転移を同時制御する新しい治療戦略

2022 Fiscal Year Research-status Report

• Project/Area Number: 22K20793
• Research Institution: Okayama University
• Principal Investigator: 友信 奈保子 岡山大学, 医歯薬学域, 助教 (80967638)
• Project Period (FY): 2022-08-31 – 2024-03-31
• Keywords: 膵臓がん / S100A11 / 転移 / 線維化

Outline of Annual Research Achievements

膵臓がんは極めて予後不良のがんであり、特にがん間質線維芽細胞が膵臓がんの治療困難性や転移を増大させることが問題となっており、間質細胞を標的とした次世代型治療法の確立が望まれている。この問題を解決するべく、我々は最近、膵臓がんが放出するS100A11タンパク質が、間質線維芽細胞膜状に発現する受容体であるRAGEにパラクラインとして作用することで、膵臓がんの成長と転移を著しく加速することを見出した。さらに、当研究室で開発したデコイ製剤であるexRAGE-Fcが膵臓がんにおける間質の増大を強力に抑制し、血中循環がん細胞（CSTs）の数の増大をも抑制するという成果を得た。
これらのことから、S100A11とそれら受容体群の遮断が、膵臓がん原発巣における間質増大と浸潤抑制に効果的であると考え、S100A11中和抗体を開発することを目的とした。本年度の研究では、現在開発中のS100A11抗体の効能を評価することとした。２量体化S100A11に特異的に結合するものを選定することができ、膵がん細胞と線維芽細胞をインベージョンアッセイに供し、開発抗体ががん細胞の浸潤を抑制したというin vitroでの成果を得たことから、開発中のS100A11の有効性を認めた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

計画がうまく進捗しほぼ期待通りの成果を得ることができているため。

Strategy for Future Research Activity

我々の開発しているS100A11抗体が線維化を抑制するかどうかについて、引き続きin vitroの系で検証する。さらに、S100A11抗体の意義、ならびに開発済みのS100A8/A9中和抗体の転移制御製剤としての有用性を高めるため、これらの抗体を膵がんマウスモデルに用い、線維化抑制並びに転移抑制の効果を発揮するかどうかを検証する。これらの成果は、膵臓がんの治療困難性を乗り越える可能性を秘めたアプローチを創出するものと考える。

Causes of Carryover

次年度の動物実験に当該費用を支出する予定であるため。

Research Products

• [Journal Article] PD-1 blockade augments CD8+ T cell dependent antitumor immunity triggered by Ad-SGE-REIC in Egfr-mutant lung cancer (2023)
  • Author(s): Nakasuka Takamasa、Ohashi Kadoaki、Nishii Kazuya、Hirabae Atsuko、Okawa Sachi、Tomonobu Nahoko、Takada Kenji、Ando Chihiro、Watanabe Hiromi、Makimoto Go、Ninomiya Kiichiro、Fujii Masanori、Kubo Toshio、Ichihara Eiki、Hotta Katsuyuki、Tabata Masahiro、Kumon Hiromi、Maeda Yoshinobu、Kiura Katsuyuki
  • Journal Title: Lung Cancer Volume: 178 Pages: 1～10
  • DOI: 10.1016/j.lungcan.2023.01.018
  • Peer Reviewed
• [Journal Article] SPRED2: A Novel Regulator of Epithelial-Mesenchymal Transition and Stemness in Hepatocellular Carcinoma Cells (2023)
  • Author(s): Gao Tong、Yang Xu、Fujisawa Masayoshi、Ohara Toshiaki、Wang Tianyi、Tomonobu Nahoko、Sakaguchi Masakiyo、Yoshimura Teizo、Matsukawa Akihiro
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Pages: 4996～4996
  • DOI: 10.3390/ijms24054996
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LOXL1 and LOXL4 are novel target genes of the Zn2+-bound form of ZEB1 and play a crucial role in the acceleration of invasive events in triple-negative breast cancer cells (2023)
  • Author(s): Daisuke Hirabayashi, Ken-ichi Yamamoto, Akihiro Maruyama, Nahoko Tomonobu, Rie Kinoshita, Youyi Chen, Ni Luh Gede Yoni Komalasari, Hitoshi Murata, Yuma Gohara, Fan Jiang, Jin Zhou, I Made Winarsa Ruma, I Wayan Sumardika, Akira Yamauchi, Futoshi Kuribayashi, Shinichi Toyooka, Yusuke Inoue, Masakiyo Sakaguchi
  • Journal Title: Frontiers in Oncology Volume: 13 Pages: -
  • DOI: 10.3389/fonc.2023.1142886
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells. (2023)
  • Author(s): Yuma Gohara, Nahoko Tomonobu, Rie Kinoshita, Junichiro Futami, Lena Audebert, Youyi Chen, Ni Luh Gede Yoni Komalasari, Fan Jiang, Chikako Yoshizawa, Hitoshi Murata, Ken-Ichi Yamamoto, Masami Watanabe, Hiromi Kumon, Masakiyo Sakaguchi
  • Journal Title: Journal of molecular medicine (Berlin, Germany) Volume: 101 Pages: 431-447
  • DOI: 10.1007/s00109-023-02292-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells (2022)
  • Author(s): Nahoko Tomonobu, Rie Kinoshita, Hidenori Wake, Yusuke Inoue, ..., Hitoshi Murata, Ken-ichi Yamamoto, I Wayan Sumardika, Youyi Chen, Junichiro Futami, Akira Yamauchi, Futoshi Kuribayashi, Eisaku Kondo, Shinichi Toyooka, Masahiro Nishibori, Masakiyo Sakaguchi
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Pages: 10300
  • DOI: 10.3390/ijms231810300
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Toll-like receptor 4 promotes bladder cancer progression upon S100A8/A9 binding, which requires TIRAP-mediated TPL2 activation (2022)
  • Author(s): Acosta Gonzalez Herik Rodrigo, Nahoko Tomonobu, Haruka Yoneda, Rie Kinoshita, ..., Hitoshi Murata, Ken-ichi Yamamoto, Junichiro Futami, Akira Yamauchi, Futoshi Kuribayashi, Yusuke Inoue, Eisaku Kondo, Shinichi Toyooka, Masahiro Nishibori, Masami Watanabe, Yasutomo Nasu, Masakiyo Sakaguchi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 634 Pages: 83-91
  • DOI: 10.1016/j.bbrc.2022.09.116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of pancreatic cancer-cell growth and metastasis in vivo by a pyrazole compound characterized as a cell-migration inhibitor by an in vitro chemotaxis assay (2022)
  • Author(s): Shuichiro Okamoto, Kei Miyano, Tominari Choshi, Norihiko Sugisawa, Takashi Nishiyama, Rika Kotouge, Masahiro Yamamura, Masakiyo Sakaguchi, Rie Kinoshita, Nahoko Tomonobu, Naoki Katase, ..., Robert M. Hoffman, Akira Yamauchi, Futoshi Kuribayashi
  • Journal Title: Biomedicine & Pharmacotherapy Volume: 155 Pages: 113733
  • DOI: 10.1016/j.biopha.2022.113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Lysyl Oxidase-Like 4 (LOXL4) Exerts an Atypical Role in Breast Cancer Progression Dependent on the Enzymatic activity (2022)
  • Author(s): Yoni Komalasari, Nahoko Tomonobu, Yuma Gohara, Rie Kinoshita, Masakiyo Sakaguchi
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] Development of therapeutic antibodies based on the elevated S100A8/A9 in tumor microenvironment (2022)
  • Author(s): Yuma Gohara, Nahoko Tomonobu, Rie Kinoshita, Kenichi Yamamoto, Masakiyo Sakaguchi
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] HRG suppresses the S100A8/A9-mediated brain tropic metastasis of melanoma cells (2022)
  • Author(s): Nahoko Tomonobu, Yoni Komalasari, Yuma Gohara, Rie Kinoshita, Kenichi Yamamoto, Akira Yamauchi, Eisaku Kondo, Shinichi Toyooka1, Masakiyo Sakaguchi
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] A critical role of S100A8/A9-NPTNb axis in the lung cancer dissemination (2022)
  • Author(s): Kenichi Yamamoto, Nahoko Tomonobu, Rie Kinoshita, Junichiro Futami, Akira Yamauchi, Shinichi Toyooka, Eisaku Kondo, Masakiyo Sakaguchi
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] A chemotaxis inhibitory agent selected using TAXIScan suppresses pancreatic cancer proliferation and metastasis (2022)
  • Author(s): Akira Yamauchi, Masahiro Yamamura, Naoki Katase, Nahoko Tomonobu, Rie Kinoshita, Masakiyo Sakaguchi, Shuichiro Okamoto
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] Binding of REIC/Dkk-3 to its receptor suppresses PD-L1 expression in triple negative breast cancer (2022)
  • Author(s): Chikako Yoshizawa, Yuma Gohara, Nahoko Tomonobu, Rie Kinoshita, Junichiro Futami, Hitoshi Murata, Kenichi Yamamoto, Masakiyo Sakaguchi
  • Organizer: 第45回日本分子生物学会年会