正常組織に影響を与えない癌幹細胞標的分子の探索

• Project/Area Number: 23K27671
• Project/Area Number (Other): 23H02980 (2023)
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund (2024); Single-year Grants (2023)
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Osaka University
• Principal Investigator: 奥崎 大介 大阪大学, 免疫学フロンティア研究センター, 特任准教授(常勤) (00346131)
• Co-Investigator(Kenkyū-buntansha): 山本 浩文 大阪大学, 大学院医学系研究科, 教授 (30322184) ; 横山 雄起 大阪大学, 大学院医学系研究科, 助教 (60615714) ; 森 正樹 東海大学, 医学部, 特任教授 (70190999)
• Project Period (FY): 2023-04-01 – 2026-03-31
• Project Status: Granted (Fiscal Year 2024)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2025: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2024: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2023: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: 癌幹細胞 / 癌精巣抗原

Outline of Research at the Start

本研究では、正常組織に影響を与えない癌幹細胞 (CSC) 標的分子の探索を行うため、癌精巣抗原 (CTA:Cancer testis antigen) に着目し、SOX2, KLF5を可視化できるマウスに作製した大腸癌組織のシングルセル解析によって導出されたCSC関連分子の中から、CTAに合致するものを絞り込むことで、副作用の問題を回避し、治療標的となりうる癌幹細胞マーカーの同定に取り組む。

Outline of Annual Research Achievements

日本人の死因の第1位は癌である。その中でも大腸癌は、高齢化や食生活の欧米化等により増加傾向にある。本邦における大腸癌の死亡率は男性で第3位、女性で第1位であり、転移や再発を起こすと治療が困難な状況であるため、さらなる対策が急務である。近年、固形癌においても自己複製能と多分化能を有し、半永久的に子孫細胞を作り続けるごく少数の癌幹細胞という概念が注目されている。癌の起点となる癌幹細胞は治療抵抗性であり、癌の根治のためにはCSCの駆除が必要であるが、未だ有効な治療法は実現されていない。本研究では、我々がこれまで開発してきた癌幹細胞遺伝子検出のための複数の実験ツールを利用し、それぞれの癌細胞のRNAseqやシングルセル解析データを比較して、共通項を見出すことで新規の癌幹細胞マーカーを見出すことを目的とした。更に正常組織では精巣以外には発現のない癌精巣抗原 (CTA:Cancer testis antigen) との合致性にも注目して、副作用のない癌幹細胞治療標的分子の同定をめざす。2023年度はCT83はODC-degron導入により作製したCSC細胞株においても高発現しており、かつCTA でもあるCT83遺伝子に着目した。CT83は正常組織では男性において主に微小管構成するチューブリンの制御を介して精子を形成する役割をもち、精巣以外の正常組織では発現がみられない。CT83が乳癌で未だ有効な治療法が確立されていないTNBC (Triple Negative Breast Cancer)細胞株において顕著な発現亢進を示すことから、CT83の乳癌におけるCSCとの関連性について解析を進めている。

Current Status of Research Progress

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

Reason

各種解析結果とCTA databaseとの照合によりCSC関連分子候補としてCT83遺伝子に着目し, TNBCでの癌幹細胞性との関わりにおいて有意な結果を得つつある。他方、臨床サンプルとの整合性を担保しつつ、SOX2発現可視化マウスを利用した遺伝子候補から3個のCSC関連遺伝子候補が、ODC degron 導入細胞からも4個のCSC関連遺伝子候補が浮かび上がってきた。

Strategy for Future Research Activity

CT83の幹細胞性への寄与を証明すべく、過剰発現、ノックダウンによって、スフェロイド形成能、活性酸素種(ROS)産生、抗癌剤抵抗性、造腫瘍性などについて検討する。新規CSC関連遺伝子についても順次遺伝子発現クローンを作製し、癌細胞性について検証を進めてゆく。

Research Products

• [Int'l Joint Research] 国立精華大学（台湾）(その他の国・地域)
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• [Journal Article] Increased anti‐oxidative action compensates for collagen tissue degeneration in vitiligo dermis (2023)
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  • Journal Title: Pigment Cell & Melanoma Research Volume: 36 Issue: 5 Pages: 355-364
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• [Journal Article] Tumor-derived semaphorin 4A improves PD-1 blocking antibody efficacy by enhancing CD8+ T-cell cytotoxicity and proliferation (2023)
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• [Journal Article] COVID-19 relapse associated with SARS-CoV-2 evasion from CD4+ T-cell recognition in an agammaglobulinemia patient. (2023)
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• [Journal Article] Single-cell analyses and host genetics highlight the role of innate immune cells in COVID-19 severity (2023)
  • Author(s): Japan COVID-19 Task Force
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• [Journal Article] Tumor-suppressive role of the musculoaponeurotic fibrosarcoma gene in colorectal cancer (2023)
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  • Journal Title: iScience Volume: 26 Issue: 4 Pages: 106478-106478
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• [Journal Article] GCN2-kinase‐mediated upregulation of ubiquitin C maintains intracellular glutamine level and tRNA Gln(CUG) charging under amino acid starvation (2023)
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• [Journal Article] Circulating miR-20b-5p and miR-330-3p are novel biomarkers for progression of atrial fibrillation: Intracardiac/extracardiac plasma sample analysis by small RNA sequencing (2023)
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  • Journal Title: PLOS ONE Volume: 18 Issue: 4 Pages: 283942-283942
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• [Journal Article] Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex (2023)
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  • Journal Title: Science Immunology Volume: 8 Issue: 81
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• [Journal Article] ONO-1301 Enhances Post-transplantation Survival of Human Induced Pluripotent Stem Cell-derived Cardiac Tissue Sheet by Promoting Angiogenesis (2023)
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  • Journal Title: The Journal of Heart and Lung Transplantation Volume: - Issue: 6 Pages: 716-716
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• [Journal Article] Single-cell RNA-seq analysis identifies distinct myeloid cells in a case with encephalitis temporally associated with COVID-19 vaccination (2023)
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• [Journal Article] JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors (2023)
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• [Journal Article] Cancer-specific tissue-resident memory T-cells express ZNF683 in colorectal cancer (2023)
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• [Journal Article] Unfolding the Bacterial Transcriptome Landscape Using Oxford Nanopore Technology Direct RNA Sequencing (2023)
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• [Journal Article] XCR1+ conventional dendritic cell-induced CD4+ T helper 1 cell activation exacerbates cardiac remodeling after ischemic myocardial injury (2023)
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• [Journal Article] Toxoplasma IWS1 Determines Fitness in Interferon-γ-Activated Host Cells and Mice by Indirectly Regulating ROP18 mRNA Expression. (2023)
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  • Journal Title: Proceedings of the National Academy of Sciences Volume: 120 Issue: 4
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• [Journal Article] In vivo induction of activin A-producing alveolar macrophages supports the progression of lung cell carcinoma (2023)
  • Author(s): Taniguchi Seiji、Matsui Takahiro、Kimura Kenji、Funaki Soichiro、Miyamoto Yu、Uchida Yutaka、Sudo Takao、Kikuta Junichi、Hara Tetsuya、Motooka Daisuke、Liu Yu-Chen、Okuzaki Daisuke、Morii Eiichi、Emoto Noriaki、Shintani Yasushi、Ishii Masaru
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• [Journal Article] Modified method for differentiation of myeloid-derived suppressor cells in vitro enhances immunosuppressive ability via glutathione metabolism (2023)
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  • DOI: 10.1016/j.isci.2022.105742
  • Peer Reviewed / Open Access
• [Journal Article] Combination of WFDC2, CHI3L1, and KRT19 in Plasma Defines a Clinically Useful Molecular Phenotype Associated with Prognosis in Critically Ill COVID-19 Patients (2023)
  • Author(s): Ebihara T, Matsubara T, Togami Y, Matsumoto H, Tachino J, Matsuura H, Kojima T, Sugihara F, Seno S, Okuzaki D, Hirata H, Ogura H.
  • Journal Title: Journal of Clinical Immunology Volume: 43 Issue: 2 Pages: 286-298
  • DOI: 10.1007/s10875-022-01386-3
  • Peer Reviewed / Open Access
• [Journal Article] S100A8 enhances IL-1β production from nasal epithelial cells in eosinophilic chronic rhinosinusitis (2023)
  • Author(s): Nakatani Ayaka、Tsuda Takeshi、Maeda Yohei、Hayama Masaki、Okuzaki Daisuke、Obata Sho、Kishikawa Toshihiro、Takeda Kazuya、Inohara Hidenori
  • Journal Title: Allergology International Volume: 72 Issue: 1 Pages: 143-150
  • DOI: 10.1016/j.alit.2022.08.005
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Tumor cell plasticity in endometrioid carcinoma is regulated by neuronal membrane glycoprotein M6?b (2022)
  • Author(s): Kusumoto Shinya、Ikeda Jun-Ichiro、Kurashige Masako、Maeno-Fujinami Etsuko、Tahara Shinichiro、Matsui Takahiro、Nojima Satoshi、Okuzaki Daisuke、Morii Eiichi
  • Journal Title: Oncology Letters Volume: 25 Issue: 2 Pages: 45-45
  • DOI: 10.3892/ol.2022.13631
  • Peer Reviewed
• [Journal Article] Identification of a unique subset of tissue-resident memory CD4 T cells in Crohn’s disease (2022)
  • Author(s): Yokoi Takehito, Murakami Mari., et al.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 120 Issue: 1
  • DOI: 10.1073/pnas.2204269120
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Peripheral‐dominant liver fibrosis and tumor distribution in a mouse model of congestive hepatopathy (2022)
  • Author(s): Kawai Hironari、Osawa Yosuke、et al.
  • Journal Title: Hepatology Research Volume: 53 Issue: 4 Pages: 370-376
  • DOI: 10.1111/hepr.13866
  • Peer Reviewed
• [Journal Article] Smoking enhances the expression of angiotensin‐converting enzyme 2 involved in the efficiency of severe acute respiratory syndrome coronavirus 2 infection (2022)
  • Author(s): Suzuki Rigel、Ono Yuki、Noshita Koji、Kim Kwang Su、Ito Hayato、Morioka Yuhei、Tamura Tomokazu、Okuzaki Daisuke、Tagawa Tetsuzo、Takenaka Tomoyoshi、Yoshizumi Tomoharu、Shimamura Teppei、Iwami Shingo、Fukuhara Takasuke
  • Journal Title: Microbiology and Immunology Volume: 67 Issue: 1 Pages: 22-31
  • DOI: 10.1111/1348-0421.13034
  • Peer Reviewed
• [Presentation] ARF6-AMAP1 経路は免疫抑制性ケモカインの発現を誘導し、免疫 回避に有利に機能する (2023)
  • Author(s): 橋本 あり、半田 悠、畑 宗一郎、奥崎 大介、麓 佳月、蔦保 暁 生、西川 義浩、児玉 裕三、平野 聡、橋本 茂、佐邊 壽孝
  • Organizer: 第82回日本癌学会学術総会
• [Presentation] CD98hc を標的とした非小細胞肺癌に対する CAR-T 細胞療法の開発 (2023)
  • Author(s): 矢賀 元、長谷川 加奈、池田 峻弥、松原 美和、寛島 隆史、木村 亨、Tansri Wibowo、奥崎 大介、貴島 晴彦、新谷 康、熊ノ郷 淳、保仙 直毅
  • Organizer: 第82回日本癌学会学術総会
• [Book] 「医学のあゆみ」第5土曜特集第288巻13号 遺伝統計学の新潮流 ─新規創薬・個別化医療への挑戦 (2024)
  • Author(s): ムハマド アル カディ,奥崎大介
  • Total Pages: 5
  • Publisher: 医歯薬出版株式会社
• [Book] 基礎研究から臨床に向けて (2023)
  • Author(s): 奥崎大介
  • Total Pages: 6
  • Publisher: BIOEX-press ダイアローグ株式会社