Development of a new treatment approach to control fibrosis and metastasis of pancreatic cancer

• Project/Area Number: 22K20793
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Okayama University
• Principal Investigator: Tomonobu Nahoko 岡山大学, 医歯薬学域, 助教 (80967638)
• Project Period (FY): 2022-08-31 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 膵臓がん / S100A11 / 転移 / 線維化

Outline of Research at the Start

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。我々はこの問題を解決するべく、膵臓がんが放出するS100A11が間質線維芽細胞のRAGEに作用し膵臓がんの成長と転移を著しく加速することを見出し、独自に開発したデコイ製剤：exRAGE-Fcが膵臓がん間質の増大を抑制したという成果を得た。S100A11とそれら受容体群の遮断が、膵臓がんにおける間質増大と浸潤抑制に効果的であると考え、本研究ではS100A11中和抗体を開発することを目的とした。本研究成果は、現状有効な治療薬が存在せず治療の困難な膵臓がんの新規治療法の確立につながると期待される。

Outline of Final Research Achievements

Pancreatic cancer is associated with poor prognosis, especially cancer stromal fibroblasts, which make treatment more challenging. In our previous study, we found that S100A11 secreted by pancreatic cancer stimulates stromal fibroblasts and accelerates the progression of pancreatic cancer. We hypothesized that blockade of S100A11 and its receptor would be effective in inhibiting stromal growth and cancer invasion in pancreatic cancer, and developed an S100A11 neutralizing antibody. Our antibody attenuated the migration and invasive ability of pancreatic cancer cells and suppressed the proliferation of fibroblasts. Therefore, our findings suggest that the efficacy of S100A11 neutralizing antibody against pancreatic cancer and stromal fibroblast augmentation.

Academic Significance and Societal Importance of the Research Achievements

間質細胞領域の占める割合の多い膵臓がんは、特に難治性である事が指摘されており、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。本研究成果から創出する新たな製剤S100A11中和抗体は将来的に治療困難とされる膵臓がんの革新的医薬品の創出にもつながる大きな展望がある。S100A11の関わる疾患は、がん細胞の増殖・転移のみならず、炎症の関わる種々臓器線維症、神経変性疾患、2型糖尿病性、自己免疫疾患など、広範にわたる。本研究により創出する製剤は、これら広範な疾患における病態発症と憎悪に対する共通の対策を提供することになり、その意義は極めて大きいものと考えている。

Research Products

• [Journal Article] Lysyl oxidase-like 4 promotes the invasiveness of triple-negative breast cancer cells by orchestrating the invasive machinery formed by annexin A2 and S100A11 on the cell surface (2024)
  • Author(s): Takahashi Tetta、Tomonobu Nahoko、Kinoshita Rie、Yamamoto Ken-ichi、Murata Hitoshi、Komalasari Ni Luh Gede Yoni、...、Honjo Tomoko、Sakaguchi Yoshihiko、Yamauchi Akira、Kuribayashi Futoshi、Kondo Eisaku、Inoue Yusuke、Futami Junichiro、Toyooka Shinichi、Zamami Yoshito、Sakaguchi Masakiyo
  • Journal Title: Frontiers in Oncology Volume: 14 Pages: 1371342-1371342
  • DOI: 10.3389/fonc.2024.1371342
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lysyl oxidase-like 4 exerts an atypical role in breast cancer progression that is dependent on the enzymatic activity that targets the cell-surface annexin A2 (2023)
  • Author(s): Sakaguchi, M., Komalasari, N. L. G. Y., Tomonobu, N., Kinoshita, R., Chen, Y., Sakaguchi, Y., Gohara, Y., Jiang, F., Yamamoto, K., Murata, H., Ruma, I. M. W., Sumardika, I. W., Zhou, J., Yamauchi, A., Kuribayashi, F., Inoue, Y., Toyooka, S.
  • Journal Title: Front. Oncol. Volume: 13 Pages: 1142907-1142907
  • DOI: 10.3389/fonc.2023.1142907
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] 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 Issue: 4 Pages: 431-447
  • DOI: 10.1007/s00109-023-02292-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SPRED2: A Novel Regulator of Epithelial-Mesenchymal Transition and Stemness in Hepatocellular Carcinoma Cells (2023)
  • Author(s): Gao T, Yang X, Fujisawa M, Ohara T, Wang T, Tomonobu N, Sakaguchi M, Yoshimura T, Matsukawa A
  • Journal Title: Int J Mol Sci Volume: 24 Issue: 5 Pages: 4996-4996
  • DOI: 10.3390/ijms24054996
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] STAT1/3 signaling suppresses axon degeneration and neuronal cell death through regulation of NAD+-biosynthetic and consuming enzymes (2023)
  • Author(s): Murata Hitoshi、Yasui Yu、Oiso Kazuma、Ochi Toshiki、Tomonobu Nahoko、Yamamoto Ken-ichi、Kinoshita Rie、Sakaguchi Masakiyo
  • Journal Title: Cellular Signalling Volume: 108 Pages: 110717-110717
  • DOI: 10.1016/j.cellsig.2023.110717
  • Peer Reviewed / Open Access
• [Journal Article] Phosphorylated SARM1 is involved in the pathological process of rotenone-induced neurodegeneration (2023)
  • Author(s): Murata Hitoshi、Phoo May Tha Zin、Ochi Toshiki、Tomonobu Nahoko、Yamamoto Ken-ichi、Kinoshita Rie、Miyazaki Ikuko、Nishibori Masahiro、Asanuma Masato、Sakaguchi Masakiyo
  • Journal Title: The Journal of Biochemistry Volume: 174 Issue: 6 Pages: 533-548
  • DOI: 10.1093/jb/mvad068
  • 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: 1142886-1142886
  • DOI: 10.3389/fonc.2023.1142886
  • 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 Issue: 18 Pages: 10300-10300
  • 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: 113733-113733
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] S100A8/A9とその新制御分子のバランスで成立するがん転移の機序解明 (2023)
  • Author(s): 友信奈保子、木下理恵、合原勇馬、Ni Luh Gede Yoni Komalasari、Fan Jiang、村田等、山本健一、山内明、近藤英作、豊岡伸一、西堀正洋、阪口政清
  • Organizer: 第95回日本組織培養学会
• [Presentation] TLR4 accelerates bladder cancer progression upon interaction with S100A8/A9 (2023)
  • Author(s): Fan Jiang、Acosta Gonzalez Herik Rodrigo、Nahoko Tomonobu、Rie Kinoshita、Yuma Gohara、Ni Luh Gede Yoni Komalasari、Ken-ichi Yamamoto、Hitoshi Murata、Akira Yamauchi、Shinichi Toyooka、Masami Watanabe、Yasutomo Nasu、Masakiyo Sakaguchi
  • Organizer: 第95回日本組織培養学会
• [Presentation] 細胞表面アネキシンA2/S100A11結合に着目した乳がん進行の機序解明 (2023)
  • Author(s): 髙橋徹多、友信奈保子、Ni Luh Gede Yoni Komalasari、合原勇馬、山本健一、木下理恵、村田等、阪口政清
  • Organizer: 第95回日本組織培養学会
• [Presentation] 糞便微生物移植治療から見出した腸内の放射菌の生理活性評価 (2023)
  • Author(s): 阪口義彦、武晃、後藤和義、竹原正也、友信奈保子、山本健一、菊池雄太、坂本光央、加藤はる、大宮直木、阪口政清、長浜政博
  • Organizer: 第95回日本組織培養学会
• [Presentation] STAT1/3シグナル経路によるNAD+代謝酵素制御を介した神経軸索変性と細胞死の抑制 (2023)
  • Author(s): 安井優、村田等、大磯和真、越智俊樹、友信奈保子、山本健一、木下理恵、阪口政清
  • Organizer: 第95回日本組織培養学会
• [Presentation] ヒトiPS細胞由来神経細胞と動物モデルを用いた軸索変性誘導分子SARM1の阻害剤開発 (2023)
  • Author(s): 村田等、安藤隆幸、安井優、越智俊樹、友信奈保子、山本健一、木下理恵、阪口政清
  • Organizer: 第95回日本組織培養学会
• [Presentation] 膵がん進展におけるS100A8/A9の機能解析と抗体による治療への応用 (2023)
  • Author(s): 宮本航大、木下理恵、小林和子、友信奈保子、山本健一、村田等、許南浩、豊岡伸一、阪口政清
  • Organizer: 第95回日本組織培養学会
• [Presentation] ヒトメラノーマ細胞の増殖と血管新生における冬虫夏草の抗腫瘍作用評価 (2023)
  • Author(s): 長﨑直也、堀井聡、I Wayan Sumardika、I Made Winarsa Ruma、友信奈保子、木下理恵、山本健一、村田等、阪口政清
  • Organizer: 第95回日本組織培養学会
• [Presentation] 亜鉛結合により活性化されるZEB1転写因子の乳がん進展における意義の解明 (2023)
  • Author(s): 山本健一、平林大輔、丸山顕嘉、友信奈保子、木下理恵、Ni Luh Gede Yoni Komalasari、村田等、合原勇馬、江帆、山内明、栗林太、豊岡伸一、井上裕介、阪口政清
  • Organizer: 第95回日本組織培養学会
• [Presentation] Lysyl oxidase-like 4 (LOXL4) empowers integrin b-1 via cross-linking of annexin A2 on the cell surface in promoting promoting breast cancer progression (2023)
  • Author(s): Ni Luh Gede Yoni Komalasari、Nahoko Tomonobu、Rie Kinoshita、Yoshihiko Sakaguchi、Yuma Gohara、Fan Jiang、Ken-ichi Yamamoto、Hitoshi Murata、Akira Yamauchi、Yusuke Inoue、Shinichi Toyooka、Masakiyo Sakaguchi
  • Organizer: 第95回日本組織培養学会
• [Presentation] REICタンパク質によるPD-L1制御を介した抗腫瘍機序の解明 (2023)
  • Author(s): 合原勇馬、友信奈保子、木下理恵、村田等、山本健一、難波正義、許南浩、公文裕巳、阪口政清
  • Organizer: 第95回日本組織培養学会
• [Presentation] 膀胱がんの進行におけるS100A8/A9に関わる分子機構の解明 (2023)
  • Author(s): 友信奈保子、木下理恵、合原勇馬、Ni Luh Gede Yoni Komalasari、二見淳一郎、山内明、近藤英作、豊岡伸一、阪口政清
  • Organizer: 第82回日本癌学会
• [Presentation] 膵がん進展におけるS100A8/A9の役割解明と治療方法の開発 (2023)
  • Author(s): 木下理恵、友信奈保子、山内明、二見淳一郎、豊岡伸一、阪口政清
  • Organizer: 第82回日本癌学会
• [Presentation] 核内PD-L1はProtein Xを抑制することでトリプルネガティブ乳がん細胞の浸潤能を促進する (2023)
  • Author(s): 合原勇馬、友信奈保子、木下理恵、山本建一、村田等、阪口政清
  • Organizer: 第82回日本癌学会
• [Presentation] Lysyl oxidase-like 4 exerts an atypical role in breast cancer progression that targets the cell-surface annexin A2 (2023)
  • Author(s): Ni Luh Gede Yoni Komalasari、友信奈保子、木下理恵、合原勇馬、山本健一、村田等、山内明、栗林太、井上裕介、豊岡伸一、阪口政清
  • Organizer: 第82回日本癌学会
• [Presentation] 新規化合物14-100とその類似体はCell-based Drug Discoveryの手法で発見された (2023)
  • Author(s): 山内明、岡本秀一郎、町支臣成、片瀬直樹、友信奈保子、木下理恵、阪口政清、山村真弘
  • Organizer: 第82回日本癌学会
• [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