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Integrated Elucidation of Genome Mutation Heterogeneity and Stem Cell Hierarchy in Breast Cancer at the Single-Cell Level

Research Project

Project/Area Number 21H02761
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 InstitutionKanazawa University

Principal Investigator

Gotoh Noriko  金沢大学, がん進展制御研究所, 教授 (10251448)

Co-Investigator(Kenkyū-buntansha) 鈴木 穣  東京大学, 大学院新領域創成科学研究科, 教授 (40323646)
岡本 康司  国立研究開発法人国立がん研究センター, 研究所, 分野長 (80342913)
廣瀬 遥香  名古屋大学, 医学系研究科, 客員研究者 (90764754)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2023: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2021: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Keywordsがん幹細胞 / トリプルネガティブ乳がん / シングルセル / 不均一性 / 治療抵抗性 / ゲノム解析 / トランスクリプトーム
Outline of Research at the Start

本研究では、研究代表者がこれまでに収集してきたヒト乳がん臨床検体由来patient-derived xenograft (PDX)を活用し、ゲノム遺伝子変異の蓄積によるがん組織の不均一性と、幹細胞性を維持するシグナルを指標とした機能的ヒエラルキーを統合させる研究を行い、がんの病態の本質を理解することを目的とする。具体的には、がん幹細胞を濃縮させた細胞分画を用いて、1細胞ごとのトランスクリプトーム並びにゲノム遺伝子変異解析を行う。さらにPDX組織切片上で、網羅的に遺伝子発現を可視化する。最終的には、真にがんを根治できる全く新しい治療コンセプトの確立を目指す。

Outline of Final Research Achievements

To unveil the most drug-resistant cell population among cancer stem cells derived from triple-negative breast cancer tissues, we performed single-cell RNA sequencing using patient samples. We named the cell population that showed characteristics similar to mammary progenitor cells "ancestor-like cancer stem cells." We demonstrated that ancestor-like cancer stem cells are the most resistant to anticancer drugs. We found that they strongly express a plasma membrane protein, FXYD3, which protects the Na-K pump on the plasma membrane. Furthermore, we showed that cardiac glycosides, Na-K inhibitors, and old drugs for cardiac failure can kill FXYD3-positive ancestor-like cancer stem cells. These results suggest that adding cardiac glycosides to preoperative adjuvant chemotherapy may prevent the recurrence of triple-negative breast cancer.

Academic Significance and Societal Importance of the Research Achievements

幹細胞の性質を持つ,いわゆる「がん幹細胞」の細胞集団の中に,抗がん剤などの治療に対して最も耐性を示す亜集団を見いだして,取り出すことに成功した。さらに,古くより心不全の治療に用いられてきた強心配糖体を用いることにより,この治療抵抗性のがん幹細胞亜集団を死滅させられることを見いだした。本知見は,強心配糖体を組み合わせた術前化学療法を行うことにより,乳がん再発を予防できる可能性を示し,乳がんの撲滅に貢献できることが期待される。今後、1細胞ごとのゲノム変異の解析を継続し、ゲノム変異によるがん細胞の不均一性と、がん幹細胞を頂点とする機能的不均一性の統合的理解へつなげる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (39 results)

All 2024 2023 2022 2021

All Journal Article (18 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 18 results,  Open Access: 18 results) Presentation (19 results) (of which Int'l Joint Research: 2 results,  Invited: 13 results) Book (2 results)

  • [Journal Article] Revealing neuropilin expression patterns in pancreatic cancer: From single-cell to therapeutic opportunities (Review)2024

    • Author(s)
      Meng Sikun、Hara Tomoaki、Sato Hiromichi、Tatekawa Shotaro、Tsuji Yoshiko、Saito Yoshiko、Hamano Yumiko、Arao Yasuko、Gotoh Noriko、Ogawa Kazuhiko、Ishii Hideshi
    • Journal Title

      Oncology Letters

      Volume: 27 Issue: 3 Pages: 1-8

    • DOI

      10.3892/ol.2024.14247

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Tolerable glycometabolic stress boosts cancer cell resilience through altered N-glycosylation and Notch signaling activation2024

    • Author(s)
      Iwamoto Shungo、Kobayashi Takashi、Hanamatsu Hisatoshi、Yokota Ikuko、Teranishi Yukiko、Iwamoto Akiho、Kitagawa Miyu、Ashida Sawako、Sakurai Ayane、Matsuo Suguru、Myokan Yuma、Sugimoto Aiyu、Ushioda Ryo、Nagata Kazuhiro、Gotoh Noriko、Nakajima Kazuki、Nishikaze Takashi、Furukawa Jun-ichi、Itano Naoki
    • Journal Title

      Cell Death & Disease

      Volume: 15 Issue: 1 Pages: 1-15

    • DOI

      10.1038/s41419-024-06432-z

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mint3-depletion-induced energy stress sensitizes triple-negative breast cancer to chemotherapy via HSF1 inactivation2023

    • Author(s)
      Tanaka Noritaka、Okada Hikari、Yamaguchi Kiyoshi、Seki Masahide、Matsubara Daisuke、Gotoh Noriko、Suzuki Yutaka、Furukawa Yoichi、Yamashita Taro、Inoue Jun-ichiro、Kaneko Shuichi、Sakamoto Takeharu
    • Journal Title

      Cell Death & Disease

      Volume: 14 Issue: 12 Pages: 815-815

    • DOI

      10.1038/s41419-023-06352-4

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters2023

    • Author(s)
      Li Mengjiao、Nishimura Tatsunori、Takeuchi Yasuto、Hongu Tsunaki、Wang Yuming、Hirose Haruka、Nomura Seitaro、Suzuki Yutaka、Okamoto Koji、Gotoh Noriko (et al. 22)
    • Journal Title

      Journal of Clinical Investigation

      Volume: 133 Issue: 22 Pages: 1-19

    • DOI

      10.1172/jci166666

    • URL

      https://pure.teikyo.jp/en/publications/d71d747a-da13-460e-9ab3-392d35ed0efc

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A model-based clustering algorithm with covariates adjustment and its application to lung cancer stratification2023

    • Author(s)
      Relvas Carlos E. M.、Nakata Asuka、Chen Guoan、Beer David G.、Gotoh Noriko、Fujita Andre
    • Journal Title

      Journal of Bioinformatics and Computational Biology

      Volume: 21 Issue: 04 Pages: 1-11

    • DOI

      10.1142/s0219720023500191

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mitochondrial one-carbon metabolic enzyme MTHFD2 facilitates mammary gland development during pregnancy2023

    • Author(s)
      Wang Yuming、Hongu Tsunaki、Nishimura Tatsunori、Takeuchi Yasuto、Takano Hiroshi、Daikoku Takiko、Yao Ryoji、Gotoh Noriko
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 674 Pages: 183-189

    • DOI

      10.1016/j.bbrc.2023.06.074

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of the mitochondria-shaping protein Opa1 restores sensitivity to Gefitinib in a lung adenocarcinomaresistant cell line2023

    • Author(s)
      Noguchi Masafumi、Kohno Susumu、Pellattiero Anna、Machida Yukino、Shibata Keitaro、Shintani Norihito、Kohno Takashi、Gotoh Noriko、Takahashi Chiaki、Hirao Atsushi、Scorrano Luca、Kasahara Atsuko
    • Journal Title

      Cell Death & Disease

      Volume: 14 Issue: 4 Pages: 1-10

    • DOI

      10.1038/s41419-023-05768-2

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Inflammatory cytokine‐enriched microenvironment plays key roles in the development of breast cancers2023

    • Author(s)
      Yasuto Takeuchi、Noriko Gotoh
    • Journal Title

      Cancer Science

      Volume: 114(5) Issue: 5 Pages: 1792-1799

    • DOI

      10.1111/cas.15734

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cryopreservation of tissues by slow-freezing using an emerging zwitterionic cryoprotectant2023

    • Author(s)
      Ishizaki Takeru、Takeuchi Yasuto、Ishibashi Kojiro、Gotoh Noriko、Hirata Eishu、Kuroda Kosuke
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 1-8

    • DOI

      10.1038/s41598-022-23913-3

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efp promotes growth of triple-negative breast cancer cells2022

    • Author(s)
      Sato Wataru、Ikeda Kazuhiro、Gotoh Noriko、Inoue Satoshi、Horie Kuniko
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 624 Pages: 81-88

    • DOI

      10.1016/j.bbrc.2022.07.071

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MCM10 compensates for Myc-induced DNA replication stress in breast cancer stem-like cells2021

    • Author(s)
      Murayama Takahiko、Takeuchi Yasuto、Li Mengjiao、Marcela Rojas‐Chaverra N.、Nishimura Tatsunori、Ikeda Kazuhiro、Horie‐Inoue Kuniko、Inoue Satoshi、Seki Masahide、Suzuki Yutaka、Sugano Sumio、Enomoto Takayuki、Tanabe Masahiko、Tada Kei‐ichiro、Okamoto Koji、Tojo Arinobu、Gotoh Noriko
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 3 Pages: 1209

    • DOI

      10.1111/cas.14776

    • URL

      https://pure.teikyo.jp/en/publications/5dc24712-a323-4664-9c98-df1ae63a9be0

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The membrane-linked adaptor FRS2β fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis2021

    • Author(s)
      Takeuchi Yasuto、Kimura N、Murayama T、Machida Y、Iejima D、Nishimura T、Terashima M、Wang Y、Li M、Sakamoto R、Yamamoto M、Itano N、Inoue Y、Ito M、Yoshida N、Inoue J、Akashi K、Saya H、Fujita K、Kuroda M、Kitabayashi I、Voon D、Suzuki Takeshi、Tojo A、Gotoh Noriko
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 118 Issue: 43 Pages: 1-12

    • DOI

      10.1073/pnas.2103658118

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A novel oral inhibitor for one-carbon metabolism and checkpoint kinase 1 inhibitor as a rational combination treatment for breast cancer2021

    • Author(s)
      Lee Jin、Chen Xiaoxi、Wang Yuming、Nishimura Tatsunori、Li Mengjiao、Ishikawa Satoko、Daikoku Takiko、Kawai Junya、Tojo Arinobu、Gotoh Noriko
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 584 Pages: 7-14

    • DOI

      10.1016/j.bbrc.2021.11.001

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MUSASHI‐2 confers resistance to third‐generation EGFR‐tyrosine kinase inhibitor osimertinib in lung adenocarcinoma2021

    • Author(s)
      Yiming Reheman、Takeuchi Yasuto、Nishimura Tatsunori、Li Mengjiao、Wang Yuming、Meguro‐Horike Makiko、Kohno Takashi、Horike Shin‐ichi、Nakata Asuka、Gotoh Noriko
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 9 Pages: 3810-3821

    • DOI

      10.1111/cas.15036

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The CD44/COL17A1 Pathway Plays a Vital Role in the Formation of Multilayered, Transformed Epithelia.2021

    • Author(s)
      Kozawa K, ,Sekai M, Ohba K, Ito S, Sako H, Maruyama T, Kakeno M , Kuromiya K, Kamasaki T, Kohashi K, Ishikawa S, Sato N, Asano S, Suzuki H, Tanimura N, Mukai Y, Gotoh N, Tanino M, Tanaka S Natsuga K, Soga T. Nakamura T, Yabuta Y, Saitou M, Ito T, Matsuura K, Tsunoda M,et.al..
    • Journal Title

      Curr Biol

      Volume: 31 Issue: 14 Pages: 3086-3097

    • DOI

      10.1016/j.cub.2021.04.078

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Xenografts derived from patients with head and neck cancer recapitulate patient tumour properties2021

    • Author(s)
      Makita Haruna、Endo Kazuhira、Kasahara Yoshiya、Nakata Asuka、Moriyama?kita Makiko?、Ishikawa Kazuya、Ueno Takayoshi、Nakanishi Yosuke、Kondo Satoru、Wakisaka Naohiro、Gotoh Noriko、Yoshizaki Tomokazu
    • Journal Title

      Oncology Letters

      Volume: 21 Issue: 5 Pages: 385-385

    • DOI

      10.3892/ol.2021.12646

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma2021

    • Author(s)
      Hirano Mitsuhito、Imai Yoichi、Kaito Yuta、Murayama Takahiko、Sato Kota、Ishida Tadao、Yamamoto Junichi、Ito Takumi、Futami Muneyoshi、Ri Masaki、Yasui Hiroshi、Denda Tamami、Tanaka Yukihisa、Ota Yasunori、Nojima Masanori、Kamikubo Yasuhiko、Gotoh Noriko、Iida Shinsuke、Handa Hiroshi、Tojo Arinobu
    • Journal Title

      Journal of Experimental & Clinical Cancer Research

      Volume: 40 Issue: 1 Pages: 110-110

    • DOI

      10.1186/s13046-021-01909-7

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway2021

    • Author(s)
      Baba Tomohisa、Yoshida Takeshi、Tanabe Yamato、Nishimura Tatsunori、Morishita Soji、Gotoh Noriko、Hirao Atsushi、Hanayama Rikinari、Mukaida Naofumi
    • Journal Title

      Cell Death & Disease

      Volume: 12 Issue: 4 Pages: 322-322

    • DOI

      10.1038/s41419-021-03587-x

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters2023

    • Author(s)
      後藤典子
    • Organizer
      第46回日本分子生物学会 シンポジウム 「最先端テクノロジーを駆使した治療抵抗性がん微小環境の解明」
    • Related Report
      2023 Annual Research Report
  • [Presentation] Heterogenous breast cancer stem cells sustain in primary and metastatic cancer stem cell niches2023

    • Author(s)
      後藤典子
    • Organizer
      第41回札幌がん国際シンポジウム
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] FXYD3 functionally demarcates an ancestral cancer stem cell subpopulation with features of drug tolerant persisters2023

    • Author(s)
      後藤典子
    • Organizer
      第18回生命医科学研究所ネットワーク国際シンポジウム
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Breast tumor microenviroment regulated by mitochondrial one-carbon metabolism2023

    • Author(s)
      後藤典子
    • Organizer
      第82回日本癌学会学術集会 Symposia on Specific Tumors “Frontiers of Breast and Ovarian Cancers
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 乳がん幹細胞とその治療戦略2023

    • Author(s)
      後藤典子
    • Organizer
      第31回日本医学会総会 Late Breaking Session
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] トリプルネガティブタイプ乳がん臨床検体のスフェロイド培養から明らかになってきた「親玉がん幹細胞」2022

    • Author(s)
      後藤典子
    • Organizer
      第4回がん三次元培養研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] トリプルネガティブタイプ乳がんの親玉がん幹細胞-root-Cancer stem cells2022

    • Author(s)
      後藤典子
    • Organizer
      日本患者由来がんモデル学会学術集会2022シンポジウム 「がん三次元培養を活用したがんの分子機構の解明」
    • Related Report
      2022 Annual Research Report
  • [Presentation] 乳がん幹細胞を標的とするがんの治療と予防戦略2022

    • Author(s)
      後藤典子
    • Organizer
      文部科学省 学術変革領域研究2022年市民公開シンポジウム「生命現象に迫るサイエンスー最先端の技術・装置で明らかにする生命のしくみー」
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Microenvironment creates premalignant mammary tissues and therapy-resistant persistent tumor cells in breast cancer2022

    • Author(s)
      後藤典子
    • Organizer
      女性科学者シンポジウム 第81回日本癌学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] トリプルネガティブ乳がん幹細胞の起源ルミナル前駆細胞は、Na+ポンプFXYD3を利用し抗がん剤耐性を獲得する2022

    • Author(s)
      後藤典子
    • Organizer
      第26回日本がん分子標的治療学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 乳がんの微小環境ニッチと腫瘍不均一性解明による新たな標的治療の可能性2022

    • Author(s)
      後藤典子
    • Organizer
      第32回日本サイトメトリー学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] FXYX3, a subunit of Na+ pump, determines the origin of triple-negative breast cancer stem-like cells, the preeminent driver of drug resistance2022

    • Author(s)
      後藤典子
    • Organizer
      The 19th Stem Cell Research Symposium
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 乳がん患者由来モデル及びマウスモデルを用いたがん幹細胞、微小環境構築の解明2021

    • Author(s)
      後藤典子
    • Organizer
      患者由来がんモデル研究会 シンポジウム「患者由来がん細胞の三次元培養を組み合わせたがんの本態解明の研究」
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] The membrane-linked adaptor FRS2beta fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis2021

    • Author(s)
      後藤典子
    • Organizer
      第44回日本分子生物学会年会 シンポジウム 「新たな3Dバイオロジーと組織解析テクノロジーを組み合わせたがん征圧への道」
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 新薬開発へ向けた産学連携の問題点と将来展望2021

    • Author(s)
      後藤典子
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Key molecular targets in cancer stem-like cells in triple-negative breast cancer2021

    • Author(s)
      後藤典子
    • Organizer
      第80回日本癌学会学術総会 コアシンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] スフェロイド・オルガノイド培養を用いた腫瘍細胞不均一性の解明2021

    • Author(s)
      後藤典子
    • Organizer
      第29回日本乳癌学会学術総会 日本癌学会合同シンポジウム「臨床を見据えたがんの基礎研究 最新のトピックス」
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 乳がん幹細胞2021

    • Author(s)
      後藤典子
    • Organizer
      第2回日本チャールス・リバー・ウエビナー
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 乳がん患者由来がん三次元培養によるマイ・メディシン2021

    • Author(s)
      後藤典子
    • Organizer
      第20回日本再生医療学会総会 「My Medicine (マイ・メディシン)―テクノロジーとともに開く新時代の医療」
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Book] がん微小環境に1細胞レベルで挑む2021

    • Author(s)
      後藤 典子、藤田 直也
    • Total Pages
      220
    • Publisher
      羊土社
    • ISBN
      9784758103961
    • Related Report
      2021 Annual Research Report
  • [Book] 医学のあゆみ 「乳腺のオルガノイドによるマイ・メディシン」―がん幹細胞研究の立場から2021

    • Author(s)
      後藤 典子
    • Total Pages
      120
    • Publisher
      医歯薬出版株式会社
    • Related Report
      2021 Annual Research Report

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Published: 2021-04-28   Modified: 2025-01-30  

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