Elucidation of molecular mechanisms of plasticity in tumor cells

• Project/Area Number: 17K19587
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology 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): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2017: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 乳癌 / 前癌状態 / 癌微小環境 / ErbB / 炎症 / シグナル伝達 / 微小環境

Outline of Final Research Achievements

Although it is known that inflammation is involved in the precancerous mammary tissues, the molecular mechanisms remain unknown. We have elucidated that FRS2beta, an adaptor for feedback inhibition of ErbB-ERK signaling, plays critical roles for evoking inflammation in the precancerous mammary tissues.
We further show that tumor cells without FRS2beta cannot grow fast due to lack of inflammation in the mammary tissues, however, they gradually adapt the condition and finally obtain ability to grow in the absence of inflammation. Epithelial-mesenchymal transdition mechanisms are involved.

Academic Significance and Societal Importance of the Research Achievements

FRS2betaは、超早期乳がんのバイオマーカーとなりえる（特許取得済み）。マンモグラフィーなどで精密検査となった症例に針生研が行われるが、このときにFRS2beta抗体で免疫染色を行うことにより、FRS2betaの発現が高ければがんの可能性が高くなる。私どもは、FRS2betaに対するモノクローナル抗体をすでに開発している。FRS2betaを標的とした予防策も期待できる。

Research Products

• [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] 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
• [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] ntratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer (2017)
  • Author(s): Yamamoto M, Sakane K, Tominaga K, Gotoh N, Niwa T, Kikuchi Y, Tada K, Goshima N, Semba K, Inoue J-I
  • Journal Title: Cancer Sci. Volume: 1082 Pages: 1210-1222
  • Peer Reviewed / Open Access
• [Journal Article] The RB-IL-6 axis controls self-renewal and endocrine therapy resistance by fine-tuning mitochondrial activity. (2017)
  • Author(s): Kitajima S, Yoshida A, Kohno S, Suzuki S, Nagatani N, Li F, Nishimoto Y, Sasaki N, Muranaka H, Wan Y, Thai T, Okahashi N, Matsuda F, Shimizu H, Nishiuchi T, Suzuki Y, Tominaga K, Gotoh N, Suzuki M, Ewen M, Barbie D, Hirose O, Tanaka T, Takahashi C
  • Journal Title: Oncogene Volume: 26 Pages: 5145-5157
  • Peer Reviewed / Open Access
• [Journal Article] An autocrine/paracrine circuit of growth differentiation factor (GDF) 15 has a role for maintenance of breast cancer stem-like cells (2017)
  • Author(s): Sasahara A, Tominga K, Nishimura T,Yano M, Kiyokawa E, Noguchi Miki, Noguchi Masakuni, Kanauchi H, Ogawa T, Minato H, Tada K, Seto Y, Tojo A, Gotoh N.
  • Journal Title: Oncotarget Volume: 8 Pages: 24869-24881
  • Peer Reviewed / Open Access
• [Journal Article] Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells (2017)
  • Author(s): Tominaga K, Shimamura T, Kimura N, Murayama T, Matsubara D, Kanauchi H, Niida A, Shimizu S, Nishioka K, Tsuji E, Yano M, Sugano S, Shimono Y, Ishii H, Saya H, Mori M, Akashi K, Tada K, Ogawa T, Tojo A, Miyano S, Gotoh N
  • Journal Title: Oncogene Volume: 36 Pages: 1276-1286
  • Peer Reviewed / Open Access
• [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
• [Presentation] Growth factor signaling controls breast cancer stem-like cells and their niche (2017)
  • Author(s): Gotoh Noriko
  • Organizer: The Korean Sciety for Biochemistry and Molecular Biology (KSBMB) International Conference 2017.
  • Invited
• [Presentation] Semaphorin signal via MICAL3 induces symmetrical cell division of cancer stem-like cells (2017)
  • Author(s): Gotoh Noriko
  • Organizer: 2017 AACR Annual Meeting, Symposium
  • Int'l Joint Research
• [Presentation] 一炭素代謝経路ミトコンドリア内酵素による肺がん幹細胞の維持 (2017)
  • Author(s): 後藤 典子
  • Organizer: 第27回日本サイトメトリー学会学術集会
  • Invited
• [Presentation] 増殖因子によるがん幹細胞とそのニッチ制御の分子機構 (2017)
  • Author(s): 後藤 典子
  • Organizer: 第9回シグナルネットワーク研究会
  • Invited
• [Presentation] ミトコンドリア１炭素代謝経路とがん幹細胞、薬剤抵抗性 (2017)
  • Author(s): 後藤 典子
  • Organizer: 第5回がんと代謝研究会
  • Invited
• [Presentation] がん関連線維芽細胞による乳がん幹細胞維持機構の解析 (2017)
  • Author(s): 後藤 典子
  • Organizer: 2017生命科学系学会合同年次総会 (ConBio2017)
  • Invited
• [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