Integrative analysis of genetical mutations and heterogeneity based on stemness in breast cancer cells

• Project/Area Number: 18H02679
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kanazawa 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): 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) ; 鈴木 穣 東京大学, 大学院新領域創成科学研究科, 教授 (40323646) ; 島村 徹平 名古屋大学, 医学系研究科, 教授 (00623943) ; 東條 有伸 東京大学, 医科学研究所, 教授 (00211681) ; 多田 敬一郎 日本大学, 医学部, 教授 (80271568)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2019: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2018: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: 1細胞 / PDX / スフェロイド / トリプルネガティブ乳がん / IGF / セマフォリン / ニューロピリン / がん幹細胞 / 乳がん / ゲノム変異 / １細胞

Outline of Final Research Achievements

To integrate the heterogeneity in cancer tissues due to accumulation of multiple mutations in genome and functional hierarchy due to different differentiation states in cancer cells, we analyzed breast cancer patient-derived xenograft models and spheroid cells. Single cell RNA sequencing following clustering analysis revealed that there are at least 2 clusters: proliferating cell cluster and non-proliferating cell cluster. We found a membrane protein FXYD3 among the highly expressing genes in the latter cell cluster and demonstrate that expression of FXYD3 is useful for distinguish the 2 populations. Furthermore, we discover novel mutations in genes that are not identified by bulk tissue analysis in cancer stem cell populations.

Academic Significance and Societal Importance of the Research Achievements

同一のがん組織内に共存する、様々なゲノム遺伝子変異をもつがん細胞集団に見られる不均一性と、がん幹細胞様細胞を中心とする機能的ヒエラルキーを統合的に解明することは重要であるが、未だ世界的にもほとんど報告がない。まず親玉がん幹細胞とそれ以外のがん幹細胞を識別できる膜蛋白が見いだされ、これまで見逃されていた親玉がん幹細胞を同定することが可能になった。また、がん幹細胞特異的な遺伝子変異も見つかり、親玉がん幹細胞を標的とし、がん根治できる分子標的の開発につながる。

Research Products

• [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, Ito S, Sakoh H, Maruyama T, Gotoh N, 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] 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] 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] 「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: 2-7
• [Journal Article] Regulation of cancer stem-like cells by cancer-associated fibroblasts (2019)
  • Author(s): 村山 貴彦、後藤 典子
  • Journal Title: Cytometry Research Volume: 29 Issue: 1 Pages: 1-6
  • DOI: 10.18947/cytometryresearch.29.1_1
  • NAID: 130007678427
  • ISSN: 0916-6920, 2424-0664
  • Year and Date: 2019-06-25
  • 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
• [Journal Article] Elucidation of Breast Cancer Tissue Diversity by Comprehensive Analysis of Minimum Unit Omics (2019)
  • Author(s): Gotoh Noriko
  • Journal Title: Impact Volume: 2019 Issue: 3 Pages: 30-32
  • DOI: 10.21820/23987073.2019.3.30
  • Peer Reviewed / Open Access
• [Journal Article] Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells (2018)
  • Author(s): Tominaga, K., Minato, H., Murayama, T., Sasahara, A., Nishimura, T., Kiyokawa, E., Kanauchi, H., Shimizu, S., Sato, A., Nishioka, K., Tsuji, E., Yano, M., Ogawa, T., Ishii, H., Mori, M., Akashi, K., Okamoto, K., Tanabe, M., Tada, K., Tojo, A., Gotoh, N.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 116 Issue: 2 Pages: 625
  • DOI: 10.1073/pnas.1806851116
  • URL: https://pure.teikyo.jp/en/publications/27ae2888-ba87-4c3b-8682-38ab484315f4
  • Peer Reviewed / Open Access
• [Journal Article] Drug discovery of anticancer drugs targeting methylenetetrahydrofolate dehydrogenase 2 (2018)
  • Author(s): Asai Ayumu、Koseki Jun、Konno Masamitsu、Nishimura Tatsunori、Gotoh Noriko、Satoh Taroh、Doki Yuichiro、Mori Masaki、Ishii Hideshi
  • Journal Title: Heliyon Volume: 4 Issue: 12 Pages: e01021-e01021
  • DOI: 10.1016/j.heliyon.2018.e01021
  • Peer Reviewed / Open Access
• [Journal Article] Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2 (2018)
  • Author(s): Nishimura Tatsunori、Nakata Asuka、Chen Xiaoxi、Nishi Kurumi、Meguro-Horike Makiko、Sasaki Soichiro、Kita Kenji、Horike Shin-ichi、Saitoh Kaori、Kato Keiko、Igarashi Kaori、Murayama Takahiko、Kohno Susumu、Takahashi Chiaki、Mukaida Naofumi、Yano Seiji、Soga Tomoyoshi、Tojo Arinobu、Gotoh Noriko
  • Journal Title: Oncogene Volume: 38 Issue: 14 Pages: 2464-2481
  • DOI: 10.1038/s41388-018-0589-1
  • Peer Reviewed / Open Access
• [Journal Article] Polyamine flux suppresses histone lysine demethylases and enhances ID1 expression in cancer stem cells (2018)
  • Author(s): Tamari K, KonnoM , Asai A, Koseki J, Hayashi K, Kawamoto K, Murai N, Matsufuji S, Isohashi F, Satoh T, Gotoh N, Tanaka S, Doki Y, Mori M, Ogawa K, Ishii H.
  • Journal Title: Cell Death Discovery Volume: 4 Issue: 104 Pages: 104-104
  • DOI: 10.1038/s41420-018-0117-7
  • Peer Reviewed / Open Access
• [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総会
  • 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79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] Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells (2019)
  • Author(s): Noriko Gotoh
  • Organizer: 19th HFSP Awardees Meeting
  • Int'l Joint Research
• [Presentation] Receptor tyrosine kinase, cancer stem cells, metabolism, breast cancer, lung cancer. (2019)
  • Author(s): Noriko Gotoh
  • Organizer: 2019 International Symposium of Advances in Cancer Stem Cell Therapeutics
  • Int'l Joint Research / Invited
• [Presentation] プリン合成系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回日本生化学会大会参加
  • 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] 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] 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] Growth factor signaIing regulates cancer stem cetts and their niche (2019)
  • Author(s): Noriko Gotoh
  • Organizer: the 6th Symposium on Novel Antitumor Agents and Individual Therapy
  • Int'l Joint Research / 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] Regulatory mechanisms for breast cancer stem-like cells and patient-derived xenograft (PDX) (2018)
  • Author(s): 後藤典子
  • Organizer: 第65回日本実験動物学会総会・シンポジウム，
  • Invited
• [Presentation] 乳がんの三次元培養とPDXを用いたがん幹細胞制御機構解明へのアプローチ (2018)
  • Author(s): 後藤典子
  • Organizer: 細胞凝集研究会2018
  • Invited
• [Presentation] Maintenance of stemness and niche environment of breast cancer cells by FRS2β, a feedback inhibitor for HER2-ERK pathway, during mammary tumorigenesis (2018)
  • Author(s): 後藤典子
  • Organizer: The 8th FUSCC-CRIKU Joint Symposium on Tumor Biology
  • Invited
• [Presentation] Analysis of regulatory mechanisms in breast cancer-stem like cells by using spheroid cultures of patient-derived cancer cells and patient-derived xenograft (PDX) models (2018)
  • Author(s): 後藤典子
  • Organizer: International Symposium on Tumor Biology in Kanazawa
  • Invited
• [Presentation] 乳がんの三次元培養とPDXを用いたがん幹細胞制御機構解明へのアプローチ (2018)
  • Author(s): 後藤典子
  • Organizer: 第41回日本分子生物学会年会・ワークショップ「新たな技術がもたらすがん治療難治性の克服にむけた新しいアプローチ」
  • Invited
• [Presentation] Growth factor and cytokine signaling regulates breast cancer stem-like cells and their niche (2018)
  • Author(s): 後藤典子
  • Organizer: 第７回Cancer Stem Cell Symposium
  • Invited
• [Book] Medical Science Digest (2019)
  • Author(s): 西村建徳、東條有伸、後藤典子
  • Total Pages: 52
  • Publisher: ニュー・サイエンス
• [Book] 患者由来がんモデルを用いたがん研究実践ガイド_乳癌などのオルガノイド培養 (2019)
  • Author(s): 村山貴彦、後藤典子
  • Total Pages: 294
  • Publisher: 羊土社
  • ISBN: 9784758122429
• [Book] 患者由来がんモデルを用いたがん研究実践ガイド_乳がんのPDX (2019)
  • Author(s): 村山貴彦、後藤典子
  • Total Pages: 294
  • Publisher: 羊土社
  • ISBN: 9784758122429
• [Book] 決定版 オルガノイド実験スタンダード_乳腺オルガノイド (2019)
  • Author(s): Chen Xiaoxi, 西村建徳，後藤典子
  • Total Pages: 372
  • Publisher: 羊土社
  • ISBN: 9784758122399
• [Book] がん幹細胞を維持する細胞内シグナル伝達系 (2018)
  • Author(s): 村山貴彦、後藤典子
  • Publisher: 文光堂
• [Book] 乳腺オルガノイド (2018)
  • Author(s): 西村建徳、Chen Xiaoxi 、後藤典子
  • Publisher: 羊土社
• [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