Elucidation of molecular mechanism of cancer stem cell niche at the very early stage aiming at cancer prevention

• Project/Area Number: 19K22557
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Kanazawa University
• Principal Investigator: Gotoh Noriko 金沢大学, がん進展制御研究所, 教授 (10251448)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 乳がん / 早期病変 / Ductal carcinoma in situ / 微小環境 / がん予防 / inflammation / precancerous tissues / NFkappaB / breast cancer / FRS2 / 超早期がん / がん幹細胞 / 炎症

Outline of Research at the Start

がんを予防し超早期に治療できれば、がんを根治することが期待されるものの、超早期の乳がん細胞が増殖を開始する分子機構が不明のため、予防法、超早期治療法は未だ存在しない。応募者は最近、前がん状態の乳腺前駆細胞がサイトカインを多く放出して炎症性の微小環境を作り、これが「超早期がん幹細胞ニッチ」としてがん幹細胞の増殖を開始させることをつきとめた。本研究では、応募者の作出した乳がんの独創的マウスモデルと、患者由来検体の培養と移植モデルを解析し、この超早期がん幹細胞ニッチの分子機構を解明する。

Outline of Final Research Achievements

We demonstrate that FRS2β an adaptor protein expressed in a small subset of epithelial cells, triggers the pro-inflammatory changes that induce stroma in premalignant mammary tissues and is responsible for the disease onset. FRS2β-deficiency in a mouse mammary tumor virus (MMTV)-ErbB2 mice markedly attenuated tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2β-deficient premalignant tissues. We found co-localization of FRS2β and the NEMO subunit of the IκB kinase (IKK) complex in early endosomes led to activation of nuclear factor-κB (NFκB) a master regulator of inflammation. Human breast cancer tissues that express higher levels of FRS2β contain more stroma. The elucidation of the FRS2β-NFκB axis uncovers a hitherto unknown molecular link between the pro-inflammatory changes and the disease onset.

Academic Significance and Societal Importance of the Research Achievements

現在，乳がんの早期病変Ductal carcinoma in situ (DCIS)はマンモグラフィで見つけることができる。しかし，その後増殖して悪性の浸潤がんになっていくかどうか見極めがつかないため，手術という侵襲性の高い治療法しか選択肢がなく，実臨床における問題となっている。本研究をさらに発展させることにより，乳がん発症前に整えられている乳腺微小環境を標的とする治療を行うことが可能になると考えられる。ひいては乳がんの発症予防，早期の治療が実現し，従来であれば乳がんにより命を落としていた人々が救われることが期待される。

Research Products

• [Journal Article] The membrane-linked adaptor FRS2β fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis (2021)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MCM10 compensates for Myc-induced DNA replication stress in breast cancer stem-like cells (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] A novel oral inhibitor for one-carbon metabolism and checkpoint kinase 1 inhibitor as a rational combination treatment for breast cancer (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] MUSASHI‐2 confers resistance to third‐generation EGFR‐tyrosine kinase inhibitor osimertinib in lung adenocarcinoma (2021)
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Xenografts derived from patients with head and neck cancer recapitulate patient tumour properties (2021)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] The CD44/COL17A1 pathway plays a vital role in the formation of transformed multi-layered epithelia (2021)
  • Author(s): Kozawa K, Sekai M, Ohba K, Gotoh N, Tanino M, Tanaka S, Natsuga K, Soga T, Nakamura T, Yabuta Y, Saitou M, Itoh T, Matsuura K, Tsunoda M, Kikumori T, Iida T, Mizutani Y, Miyai Y, Enomoto A, Fujita Y.
  • Journal Title: Curr Biol Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] 「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
  • Journal Title: 医学のあゆみ Volume: 276(5) Pages: 21810-21816
• [Journal Article] Cancer treatments targeting mitochondrial enzymes involved in one-carbon metabolism (2020)
  • Author(s): 西村 建徳、東條 有伸、後藤 典子
  • Journal Title: Cytometry Research Volume: 30 Issue: 2 Pages: 9-13
  • DOI: 10.18947/cytometryresearch.30.2_9
  • NAID: 130007952546
  • ISSN: 0916-6920, 2424-0664
  • Year and Date: 2020-12-11
  • Peer Reviewed / Open Access
• [Journal Article] Upregulation of S100A10 in metastasized breast cancer stem cells (2020)
  • Author(s): Yanagi Hisano、Watanabe Takashi、Nishimura Tatsunori、Hayashi Takanori、Kono Seishi、Tsuchida Hitomi、Hirata Munetsugu、Kijima Yuko、Takao Shintaro、Okada Seiji、Suzuki Motoshi、Imaizumi Kazuyoshi、Kawada Kenji、Minami Hironobu、Gotoh Noriko、Shimono Yohei
  • Journal Title: Cancer Science Volume: 111 Issue: 12 Pages: 4359-4370
  • DOI: 10.1111/cas.14659
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mint3 depletion restricts tumor malignancy of pancreatic cancer cells by decreasing SKP2 expression via HIF-1 (2020)
  • Author(s): Kanamori Akane、Matsubara Daisuke、Saitoh Yurika、Fukui Yuya、Gotoh Noriko、Kaneko Shuichi、Seiki Motoharu、Murakami Yoshinori、Inoue Jun-ichiro、Sakamoto Takeharu
  • Journal Title: Oncogene Volume: 39 Issue: 39 Pages: 6218-6230
  • DOI: 10.1038/s41388-020-01423-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Proliferation‐associated long noncoding RNA, TMPO‐AS1 , is a potential therapeutic target for triple‐negative breast cancer (2020)
  • Author(s): Mitobe Yuichi、Ikeda Kazuhiro、Sato Wataru、Kodama Yukinobu、Naito Mitsuru、Gotoh Noriko、Miyata Kanjiro、Kataoka Kazunori、Sasaki Hitoshi、Horie‐Inoue Kuniko、Inoue Satoshi
  • Journal Title: Cancer Science Volume: 1 Issue: 7 Pages: 1-20
  • DOI: 10.1111/cas.14498
  • Peer Reviewed / Open Access
• [Journal Article] Large miRNA survival analysis reveals a prognostic four-biomarker signature for triple negative breast cancer (2020)
  • Author(s): Andrade Fernando、Nakata Asuka、Gotoh Noriko、Fujita Andre
  • Journal Title: Genetics and Molecular Biology Volume: 43 Issue: 1 Pages: 1-11
  • DOI: 10.1590/1678-4685-gmb-2018-0269
  • Peer Reviewed / Open Access
• [Journal Article] 微小環境と治療抵抗性メカニズム (2020)
  • Author(s): 村山貴彦、後藤典子
  • Journal Title: CANCER BOARD of the BREAST Volume: 6(2) Pages: 102-104
• [Journal Article] がん幹細胞とそのニッチ (2020)
  • Author(s): 後藤典子
  • Journal Title: 医学のあゆみ Volume: 273 Pages: 362-367
  • Peer Reviewed / Open Access
• [Journal Article] がん幹細胞とその微小環境および治療への展望 (2020)
  • Author(s): 後藤典子
  • Journal Title: Life Science Connect Volume: 1 Pages: 2-7
  • Peer Reviewed / Open Access
• [Journal Article] Drug resistance mechanisms of cancer stem-like cells and their therapeutic potential as drug targets (2019)
  • Author(s): Murayama Takahiko、Gotoh Noriko
  • Journal Title: Cancer Drug Resistance Volume: 2 Pages: 457-470
  • DOI: 10.20517/cdr.2019.36
  • Peer Reviewed / Open Access
• [Journal Article] Patient-Derived Xenograft Models of Breast Cancer and Their Application (2019)
  • Author(s): Murayama Takahiko、Gotoh Noriko
  • Journal Title: Cells Volume: 8 Issue: 6 Pages: 621-621
  • DOI: 10.3390/cells8060621
  • Peer Reviewed / Open Access
• [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」
  • Invited
• [Presentation] The membrane-linked adaptor FRS2beta fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis (2021)
  • 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」
  • 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
  • Invited
• [Presentation] Key molecular targets in cancer stem-like cells in triple-negative breast cancer (2021)
  • 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
  • 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」
  • 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
  • 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」
  • 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回日本再生医療治療学会
  • Invited
• [Presentation] 乳がん患者由来がん三次元培養からがん幹細胞の不均一性に迫る (2020)
  • Author(s): 後藤典子
  • Organizer: 患者由来がんモデル講演会
  • Invited
• [Presentation] がん幹細胞を標的とした治療戦略 (2020)
  • Author(s): 後藤典子
  • Organizer: 第24回日本がん分子標的治療学会
  • Invited
• [Presentation] がん幹細胞標的治療の実現への具体的な道筋 (2020)
  • Author(s): 後藤典子
  • Organizer: 第78回日本癌学会学術総会
  • Invited
• [Presentation] 固形がんのPatient-derived xenograft (PDX) (2020)
  • Author(s): 後藤典子
  • Organizer: 第78回日本癌学会学術総会
  • Invited
• [Presentation] 固形がんの１細胞解析-乳がん- (2020)
  • Author(s): 後藤典子
  • Organizer: 第29回日本サイトメトリー学会学術集会
  • Invited
• [Presentation] 乳がん臨床検体由来がん幹細胞濃縮細胞群の1細胞解析 (2019)
  • Author(s): 後藤典子
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Presentation] Growth factor signaling regulates cancer stem cells and their niche (2019)
  • Author(s): Noriko Gotoh
  • Organizer: The 6th Symposium on Anti-tumor Agents and Individual Therapy
  • Int'l Joint Research / Invited
• [Presentation] 乳がん三次元培養を用いたがんの微小環境、不均一性の解明 (2019)
  • Author(s): 後藤典子
  • Organizer: 第3回がん三次元培養研究会
  • Invited
• [Presentation] 乳がん患者検体由来三次元培養細胞とがん間質細胞の共培養系を用いたがん幹細胞ニッチシグナルの解析 (2019)
  • Author(s): 後藤典子
  • Organizer: 第78回日本癌学会学術総会
  • Invited
• [Presentation] One carbon metabolic enzymes play important roles for cancer cells and cancer stem-like cells (2019)
  • Author(s): Noriko Gotoh
  • Organizer: 3rd World Congress on Cancer
  • Int'l Joint Research / Invited
• [Presentation] プリン合成経路にあるミトコンドリア内酵素MTHFD2は、がん幹細胞性とゲフィチニブ耐性を賦与する (2019)
  • Author(s): 後藤典子
  • Organizer: 第92回日本生化学大会
  • Invited
• [Presentation] The replicative factor MCM10 maintains patient-derived breast cancer stem-like cells that constitutively experience DNA replicative stress (2019)
  • Author(s): 後藤典子
  • Organizer: 患者由来がんモデル-基礎研究から臨床応用まで
  • Invited
• [Presentation] 微小環境と治療抵抗性メカニズム (2019)
  • Author(s): 後藤典子
  • Organizer: 第27回日本乳癌学会学術集会
  • Invited
• [Presentation] 乳がんの1細胞解析 (2019)
  • Author(s): 後藤典子
  • Organizer: 第29日本サイトメトリー学会学術集会
  • Invited
• [Presentation] Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells (2019)
  • Author(s): Noriko Gotoh
  • Organizer: Symposium: The State-of-the-Art 3D Tissue Culture & Organoids
  • Int'l Joint Research / 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
• [Book] 医学のあゆみ (2021)
  • Author(s): 後藤 典子
  • Total Pages: 120
  • Publisher: 医歯薬出版株式会社
• [Remarks] 金沢大学がん進展制御研究所 分子病態研究分野 後藤研
  • URL: http://bunshibyotai.w3.kanazawa-u.ac.jp/
• [Patent(Industrial Property Rights)] がん幹細胞の分画方法 (2021)
  • Inventor(s): 後藤典子、西村建徳、Li Mengjiao
  • Industrial Property Rights Holder: 後藤典子、西村建徳、Li Mengjiao
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-012049
  • Filing Date: 2021