Development of innovative therapies for oral cancer metastasis targeting the formation of pre-metastasis niches by exosomes

• Project/Area Number: 21K10048
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Kumamoto University
• Principal Investigator: Yoshuda Ryoji 熊本大学, 大学院生命科学研究部(医), 准教授 (10632458)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 口腔扁平上皮癌 / エクソソーム / マイクロRNA / 腫瘍微小環境 / PDXモデル / 口腔がん / 前転移ニッチ / プロテオミクス

Outline of Research at the Start

口腔扁平上皮癌 (Oral squamous cell carcinoma: OSCC) は口腔癌の80%を占める疾患であり、“転移”は重要な因子の一つである。転移の成立には腫瘍細胞が有する浸潤・転移能のみならず、転移臓器における微小環境調整によって“前転移ニッチ”を形成する能力も重要であることが明らかとなっている。近年、“エクソソーム”が転移臓器の“前転移ニッチ”の形成を制御し、転移の成立に深く関わることが明らかとなってきた。本研究ではエクソソームによる“前転移ニッチ形成”を中心とした転移制御メカニズムを解明し、口腔扁平上皮癌の“転移”制御を目指した、革新的診断法・治療法の確立を目指す。

Outline of Final Research Achievements

We conducted a study to develop an innovative treatment for oral cancer metastasis by targeting the formation of a pre-metastatic niche by exosomes. We found that PD-L1 is characteristically expressed in blood exosomes of patients with recurrent or metastatic oral cancer, and reported that it correlates with the therapeutic efficacy and prognosis of immunotherapy. We also performed multilayer omics analysis of exosomes extracted from patient sera, found miRNA-X associated with metastasis, and verified its clinical significance, which is now being submitted to an international journal. Furthermore, we established a highly metastatic subclone from a PDX cell line derived from an oral cancer patient and found multiple characteristic molecular expression profiles as a result of proteomic analysis. We are currently analyzing the biological significance of these molecules in the formation of the pre-metastatic niche.

Academic Significance and Societal Importance of the Research Achievements

高転移性口腔癌による前転移ニッチ形成に着目して口腔がん転移の病態解明を目指した研究はほとんどなく、本研究成果は限界を迎えつつある口腔がんの転移診断や治療法開発に大きなパラダイムシフトをもたらし得ると考えられる。また、本研究の過程で、効率的にエクソソームを回収するキットの有用性や、口腔がんにおける体液診断の有用性についても証明することができた。以上の成果は、今後の研究を進める上での大きな成果であり、口腔がんの病態解明に寄与するだけでなく、他癌腫における高転移性腫瘍細胞の制御機構解明にも新たな知見をもたらし、その診断・治療法開発に大きく貢献すると考えられる。

Research Products

• [Journal Article] Programmed death-ligand 1-expressing extracellular vesicles are a prognostic factor in patients with oral squamous cell carcinoma treated with immune checkpoint inhibitors (2023)
  • Author(s): Seki Yuki、Yamana Keisuke、Yoshida Ryoji、Inoue Junki、Shinohara Kosuke、Oyama Toru、Kubo Ryuta、Nagata Masashi、Kawahara Kenta、Hirayama Masatoshi、Takahashi Nozomu、Nakamoto Masafumi、Hirosue Akiyuki、Kariya Ryusho、Okada Seiji、Nakayama Hideki
  • Journal Title: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology Volume: in press Issue: 4 Pages: 518-525
  • DOI: 10.1016/j.ajoms.2023.12.007
  • Peer Reviewed / Open Access
• [Journal Article] FOXM1-Mediated Regulation of Reactive Oxygen Species and Radioresistance in Oral Squamous Cell Carcinoma Cells (2023)
  • Author(s): Takeshita Hisashi、Yoshida Ryoji、Inoue Junki、Ishikawa Kohei、Shinohara K、Hirayama M、Oyama T、Kubo R、Yamana K、Nagao Y、Gohara S、Sakata J、Nakashima H、Matsuoka Y、Nakamoto M、Hirayama M、Kawahara K、Takahashi N、Hirosue A、Kuwahara Y、Fukumoto M、Toya R、Murakami R、Nakayama H
  • Journal Title: Laboratory Investigation Volume: 103 Issue: 5 Pages: 100060-100060
  • DOI: 10.1016/j.labinv.2022.100060
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The antioxidative stress regulator Nrf2 potentiates radioresistance of oral squamous cell carcinoma accompanied with metabolic modulation (2022)
  • Author(s): Matsuoka Yuichiro、Yoshida Ryoji、Kawahara Kenta、Sakata Junki、Arita Hidetaka、Nkashima Hikaru、Takahashi Nozomu、Hirayama Masatoshi、Nagata Masashi、Hirosue Akiyuki、Kuwahara Yoshikazu、Fukumoto Manabu、Toya Ryo、Murakami Ryuji、Nakayama Hideki
  • Journal Title: Laboratory Investigation Volume: 102 Issue: 8 Pages: 896-907
  • DOI: 10.1038/s41374-022-00776-w
  • Peer Reviewed / Open Access
• [Journal Article] An oncolytic virus as a promising candidate for the treatment of radioresistant oral squamous cell carcinoma. (2022)
  • Author(s): Gohara S, Shinohara K, Yoshida R, Kariya R, Tazawa H, Hashimoto M, Inoue J, Kubo R, Nakashima H, Arita H, Kawaguchi S, Yamana K, Nagao Y, Iwamoto A, Sakata J, Matsuoka Y, Takeshita H, Hirayama M, Kawahara K, Nagata M, Hirosue A, Kuwahara Y, Fukumoto M, Okada S, Urata Y, Fujiwara T, and Nakayama H.
  • Journal Title: Molecular Therapy Oncolytics Volume: 27 Pages: 141-156
  • DOI: 10.1016/j.omto.2022.10.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extracellular vesicles derived from radioresistant oral squamous cell carcinoma cells contribute to the acquisition of radioresistance via the miR‐503‐3p‐BAK axis (2021)
  • Author(s): K Yamana,J Inoue,R Yoshida,J Sakata,H Nakashima,H Arita,S Kawaguchi,S Gohara,Y Nagao,H Takeshita,M Maeshiro,R Liu,Y Matsuoka,M Hirayama,K Kawahara,M Nagata,A Hirosue,R Toya,R Murakami,Y Kuwahara,M Fukumoto,H Nakayama
  • Journal Title: Journal of Extracellular Vesicles Volume: 10 Issue: 14
  • DOI: 10.1002/jev2.12169
  • Peer Reviewed / Open Access
• [Presentation] Investigating the usefulness of the risk score for late metastasis in cT1-2N0 tongue cancer (2023)
  • Author(s): 井上淳貴、吉田遼司、竹下尚志、大山徹、石川紘平、関祐紀、篠原光佑、諸富静香、川原健太、平山真敏、高橋望、中山秀樹
  • Organizer: 第82回日本癌学会学術総会
• [Presentation] Development of a prediction system for delayed neck metastases of tongue cancer (2023)
  • Author(s): Junki Inoue, Ryoji Yoshida, Junki Sakata, Kenta Kawahara, Masatoshi Hirayama, Nozomu Takahashi, Hideki Nakayama
  • Organizer: 第47回頭頸部癌学会総会