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Functional Analysis of Cytoplasmic Nucleic Acid Sensor in the Tumor Microenvironment

Research Project

Project/Area Number 19H03507
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionJapanese Foundation for Cancer Research

Principal Investigator

TAKAHASHI Akiko  公益財団法人がん研究会, がん研究所 細胞老化プロジェクト, プロジェクトリーダー (60380052)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2021: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords細胞老化 / SASP / 核酸センサー / 腫瘍微小環境 / がん微小環境
Outline of Research at the Start

近年、DNA/RNAハイブリッドが腫瘍の発症や悪性化に関与することが示唆されているが、その制御機構は不明である。本研究は、腫瘍微小環境中のがん細胞や老化細胞においてDNA/RNAハイブリッドが過剰に産生され蓄積する分子メカニズムを解析してその核酸センサーを同定し、さらにがん微小環境における核酸センサーの機能を解明し制御の方策を得ることで、がんの病態の理解と制御を目指す。

Outline of Final Research Achievements

Cellular senescence is important tumor suppressive mechanisms. However, senescent cells secrete various inflammatory SASP (senescence-associated secretory phenotype) factors, which promote cancer development and malignancy. In this study, we found that the expression level of ribonuclease significantly decreases in senescent cells, resulting in the production of DNA/RNA hybrid and accumulation of ribonucleoside monophosphate in genomic DNA, which promotes genomic instability. Consequently, cytoplasmic nucleotide fragments are accumulated in the cytoplasm and cause the activation of cytoplasmic sensors, thereby leading to SASP induction in the cancer microenvironment.

Academic Significance and Societal Importance of the Research Achievements

近年、加齢性疾患の原因となる老化細胞やSASPを治療標的とするSenolyticsの開発が世界的に進められている。そのため、老化細胞でSASPがおこる分子メカニズムを明らかにすることは疾患制御の観点から重要であると考えられている。本研究は、SASPの引き金となる細胞質核酸センサーの活性化には、老化細胞におけるRNA分解酵素の機能低下が重要であることを見出しており、今後、核酸センサーを標的とした新たな治療方法やSASPを抑制するSenomorphicsの開発に繋がることが期待される。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (48 results)

All 2022 2021 2020 2019 Other

All Int'l Joint Research (1 results) Journal Article (13 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 10 results,  Open Access: 9 results) Presentation (23 results) (of which Int'l Joint Research: 8 results,  Invited: 15 results) Book (10 results) Remarks (1 results)

  • [Int'l Joint Research] University of Miami School of Medicine(米国)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Pericentromeric repetitive ncRNA regulates chromatin interaction and inflammatory gene expression2022

    • Author(s)
      Miyata Kenichi、Takahashi Akiko
    • Journal Title

      Nucleus

      Volume: 277 Issue: 1 Pages: 74-78

    • DOI

      10.1080/19491034.2022.2034269

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cancer-Specific Targeting of Taurine-Upregulated Gene 1 Enhances the Effects of Chemotherapy in Pancreatic Cancer2021

    • Author(s)
      Tasaki Y, Suzuki M, Katsushima K, Shinjo K, Iijima K, Murofushi Y, Naiki-Ito A, Hayashi K, Qiu C, Takahashi A, Tanaka Y, Kawaguchi T, Sugawara M, Kataoka T, Naito M, Miyata K, Kataoka K, Noda T, Gao W, Kataoka H, Takahashi S, Kimura K, Kondo Y.
    • Journal Title

      Cancer Research

      Volume: - Issue: 7 Pages: 1654-1666

    • DOI

      10.1158/0008-5472.can-20-3021

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer2021

    • Author(s)
      Kenichi Miyata, Yoshinori Imai, Satoshi Hori, Mika Nishio, Tze Mun Loo, Ryo Okada, Liying Yang, Tomoyoshi Nakadai, et. al.
    • Journal Title

      Proc Natl Acad Sci U S A

      Volume: 118 Issue: 35

    • DOI

      10.1073/pnas.2025647118

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion2021

    • Author(s)
      Okumura Shintaro、Konishi Yusuke、Narukawa Megumi、Sugiura Yuki、Yoshimoto Shin、Arai Yuriko、Sato Shintaro、Yoshida Yasuo、Tsuji Shunya、Uemura Ken、Wakita Masahiro、Matsudaira Tatsuyuki、Matsumoto Tomonori、Kawamoto Shimpei、Takahashi Akiko、Itatani Yoshiro、Miki Hiroaki ら
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 5674-5674

    • DOI

      10.1038/s41467-021-25965-x

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination2021

    • Author(s)
      Yasuda T, Koiwa M, Yonemura A, Miyake K, Kariya R, Kubota S, Yokomizo-Nakano T, Yasuda-Yoshihara N, Uchihara T, Itoyama R, Bu L, Fu L, Arima K, Izumi D, Iwagami S, Eto K, Iwatsuki M, Baba Y, Yoshida N, Ohguchi H, Okada S, Matsusaki K, Sashida G, Takahashi A, Tan P, Baba H, Ishimoto T.
    • Journal Title

      Cell Reports

      Volume: 34 Issue: 8 Pages: 108779-108779

    • DOI

      10.1016/j.celrep.2021.108779

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Senescence-associated extracellular vesicle (SA-EV) release plays a role in senescence-associated secretory phenotype (SASP) in age-associated diseases.2021

    • Author(s)
      Tanaka, Y. and Takahashi, A.
    • Journal Title

      J. Biochem.

      Volume: 169(2) Issue: 2 Pages: 147-153

    • DOI

      10.1093/jb/mvaa109

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells.2020

    • Author(s)
      Wakita M, Takahashi A, Sano O, Loo TM, Imai Y, Narukawa M, Iwata H, Matsudaira T, Kawamoto S, Ohtani N, Yoshimori T, Hara E.
    • Journal Title

      Nat Commun

      Volume: 1935 Issue: 1 Pages: 1935-1935

    • DOI

      10.1038/s41467-020-15719-6

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses2020

    • Author(s)
      Hitomi Kazuhiro、Okada Ryo、Loo Tze Mun、Miyata Kenichi、Nakamura Asako J.、Takahashi Akiko
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 10 Pages: 3720-3720

    • DOI

      10.3390/ijms21103720

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] γ‐Glutamyltranspeptidase (GGT)‐Activatable Fluorescence Probe for Durable Tumor Imaging2020

    • Author(s)
      Obara Rui、Kamiya Mako、Tanaka Yoko、Abe Atsuki、Kojima Ryosuke、Kawaguchi Tokuichi、Sugawara Minoru、Takahashi Akiko、Noda Tetsuo、Urano Yasuteru
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 60 Issue: 4 Pages: 2125-2129

    • DOI

      10.1002/anie.202013265

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 細胞老化とエクソソーム2020

    • Author(s)
      人見一寛、高橋暁子
    • Journal Title

      医学のあゆみ

      Volume: 272 Pages: 303-307

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Cellular senescence and senescence‐associated secretory phenotype via the cGAS‐STING signaling pathway in cancer2019

    • Author(s)
      Loo Tze Mun、Miyata Kenichi、Tanaka Yoko、Takahashi Akiko
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 2 Pages: 304-311

    • DOI

      10.1111/cas.14266

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] SASP誘導の分子機構とその役割2019

    • Author(s)
      高橋暁子、原英二
    • Journal Title

      実験医学

      Volume: 37 Pages: 1735-1739

    • Related Report
      2019 Annual Research Report
  • [Journal Article] 老化とがんにおけるSASPの役割とメカニズム2019

    • Author(s)
      宮田憲一、高橋暁子
    • Journal Title

      臨床・免疫・アレルギー科

      Volume: 72 Pages: 214-219

    • Related Report
      2019 Annual Research Report
  • [Presentation] がん微小環境における細胞老化の機能2022

    • Author(s)
      高橋暁子
    • Organizer
      第40回腫瘍病理セミナー・北信がんプロFD講演会・金沢女性研究者フォーラム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Molecular mechanisms of inflammatory gene expression in senescent cells2022

    • Author(s)
      Akiko Takahashi
    • Organizer
      The 12th BRI International Symposium「The old and new crossroads of microorganisms and neurodegeneration」
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 細胞老化と発がん2022

    • Author(s)
      高橋暁子
    • Organizer
      第40回Cytoprotection研究会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 老化細胞が分泌する細胞外小胞の生体機能の解析2021

    • Author(s)
      高橋暁子
    • Organizer
      第94回日本内分泌学会学術総会 YECセミナー 「エクソソーム最前線」
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 細胞老化とSASPの新知見2021

    • Author(s)
      高橋暁子
    • Organizer
      第21回日本抗加齢医学会総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Analysis of cellular senescence and breast cancer recurrence in the cancer microenvironment2021

    • Author(s)
      高橋暁子、宮田憲一
    • Organizer
      第80回日本癌学会学術総会 腫瘍別シンポジウム4乳がん 「Late recurrenceの基礎と臨床」
    • Related Report
      2021 Annual Research Report
  • [Presentation] エクソソームの診断と治療への展開2021

    • Author(s)
      高橋暁子
    • Organizer
      第80回日本癌学会学術総会 モーニングレクチャー21
    • Related Report
      2021 Annual Research Report
  • [Presentation] Chromatin Dynamics and Inflammatory Gene Expression in Cellular Senescence2021

    • Author(s)
      高橋暁子
    • Organizer
      第94回日本生化学会大会 シンポジウム 2S07e 細胞老化の新潮流
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Novel Regulatory Mechanism of SASP in Cellular Senescence2021

    • Author(s)
      高橋暁子
    • Organizer
      第44回日本分子生物学会大会 シンポジウム 「Continuity of the life and Aging」
    • Related Report
      2021 Annual Research Report
  • [Presentation] Pericentromeric noncoding RNA induces inflammatory gene expression in cellular senescence2021

    • Author(s)
      Akiko Takahashi, Kenichi Miyata, Eiji Hara
    • Organizer
      The 6th International Cell Senescence Association
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Biology of small extracellular vesicles secreted from senescent cells2021

    • Author(s)
      Akiko Takahashi, Kenichi Miyata, Yoko Tanaka
    • Organizer
      The International Chemical Congress of Pacific Basin Societies 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 細胞老化による核膜構造変化と加齢性疾患の関わり2021

    • Author(s)
      高橋暁子
    • Organizer
      第126回日本解剖学会総会・全国学術集会/第98回日本生理学会大会 合同大会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] The Analysis of Epigenetic alteration in cellular senescence and cancer2020

    • Author(s)
      高橋暁子, 宮田憲一, 羅智文, 菅原祥
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] A molecular link between cellular senescence and age-relevant disorders」DNA damage provokes senescence-associated secretory phenotype and extracellular vesicle release from senescent cells2020

    • Author(s)
      高橋暁子
    • Organizer
      第63回日本放射線影響学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Molecular Mechanism and Biofunction of SASP2020

    • Author(s)
      高橋暁子
    • Organizer
      第43回日本分子生物学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Analysis of small extracellular vesicles in aging and cancer2020

    • Author(s)
      Akiko Takahashi
    • Organizer
      UKEV 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] The biology of Cellular Senescence in age-related diseases2020

    • Author(s)
      Akiko Takahashi
    • Organizer
      GIAR Sympodium 2020
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] The biological function of exosomes secreted from senescent cells in the cancer microenvironment2019

    • Author(s)
      Akiko Takahashi
    • Organizer
      第18回American Association for Cancer Research AACR/JCA Joint Session: Exosomes in Diagnosis and Treatment of Cancer
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] The biological function of SASP factors in cancer2019

    • Author(s)
      Akiko Takahashi
    • Organizer
      Korean Society for Biochemistry and Molecular Biology International Conference
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 老化細胞分泌因子(SASP因子)の生体における機能解析2019

    • Author(s)
      高橋暁子
    • Organizer
      第19回日本抗加齢医学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 老化細胞が分泌する細胞外微粒子の解析2019

    • Author(s)
      高橋暁子
    • Organizer
      第37回物性物理化学研究会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] The roles of Cellular Senescence in the cancer microenvironment2019

    • Author(s)
      Akiko Takahashi
    • Organizer
      Tohoku Forum for Creativity, Thematic Program 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 細胞老化と加齢性疾患の関り2019

    • Author(s)
      高橋暁子
    • Organizer
      北海道大学部局横断シンポジウム
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Book] 実験医学 「老化細胞を標的としたSenolyticsへの挑戦」企画2022

    • Author(s)
      高橋暁子
    • Total Pages
      7
    • Publisher
      羊土社
    • ISBN
      9784758125543
    • Related Report
      2021 Annual Research Report
  • [Book] 生物の寿命延長2022

    • Author(s)
      田中久通、高橋暁子
    • Total Pages
      460
    • Publisher
      エヌ・ティー・エス
    • ISBN
      9784860437732
    • Related Report
      2021 Annual Research Report
  • [Book] 医学のあゆみ2021

    • Author(s)
      宮田憲一、高橋暁子
    • Total Pages
      6
    • Publisher
      医歯薬出版
    • Related Report
      2021 Annual Research Report
  • [Book] 実験医学2021

    • Author(s)
      高橋暁子、原 英二
    • Total Pages
      4
    • Publisher
      羊土社
    • ISBN
      9784758125444
    • Related Report
      2021 Annual Research Report
  • [Book] 実験医学増刊号「細胞外小胞の生物学」2021

    • Author(s)
      千葉正智、三澤知香、田中陽子、高橋暁子
    • Total Pages
      7
    • Publisher
      羊土社
    • ISBN
      9784758103992
    • Related Report
      2021 Annual Research Report
  • [Book] 新臨床腫瘍学(改訂第4版)2021

    • Author(s)
      日本臨床腫瘍学会
    • Total Pages
      760
    • Publisher
      南江堂
    • ISBN
      9784524261871
    • Related Report
      2021 Annual Research Report
  • [Book] Drug Delivery System2021

    • Author(s)
      三澤知香、田中陽子、高橋暁子
    • Total Pages
      8
    • Publisher
      日本DDS学会
    • Related Report
      2020 Annual Research Report
  • [Book] バイオマテリアル学会誌2020

    • Author(s)
      菅原祥, 宮田憲一, 田中久道, 高橋暁子
    • Total Pages
      6
    • Publisher
      日本バイオマテリアル学会
    • Related Report
      2020 Annual Research Report
  • [Book] 腎臓内科2020

    • Author(s)
      荒谷紗絵, 田中陽子, 酒井直行, 高橋暁子
    • Total Pages
      7
    • Publisher
      科学評論社
    • ISBN
      9784498224742
    • Related Report
      2020 Annual Research Report
  • [Book] 老年内科2020

    • Author(s)
      羅智文, 菅原祥, 高橋暁子
    • Total Pages
      9
    • Publisher
      科学評論社
    • Related Report
      2020 Annual Research Report
  • [Remarks] 公益財団法人がん研究会がん研究所細胞老化プロジェクトホームページ

    • URL

      https://www.jfcr.or.jp/laboratory/department/senescence/www/index.html

    • Related Report
      2019 Annual Research Report

URL: 

Published: 2019-04-18   Modified: 2023-12-25  

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