Elucidation of breast cancer tissue diversity by integration analysis of minimum unit omics

• Project/Area Number: 15H04294
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• 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): 東條 有伸 東京大学, 医科学研究所, 教授 (00211681) ; 島村 徹平 名古屋大学, 医学系研究科, 特任准教授 (00623943) ; 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)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2017: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: Single cell / cancer stem cells / breast cancer, / semaphoring, neuropilin / がん幹細胞 / 乳がん / RNAシークエンス / シングルセル / 幹細胞 / 1細胞 / スフェロイド培養 / 遺伝子発現 / neuropilin / PDXモデル

Outline of Final Research Achievements

Cancer tissues are composed of very heterogenous cell populations, including cancer stem cells, progenitor cancer cells and differentiated cancer cells. It is thus important to clarify the characteristics of each cell type at single cell levels. The aim of this study to clarify the molecular mechanisms how cancer stem cells are maintained in the caner stem cell niche by analyzing transcriptome at single cell levels. We have clarified the semaphorin-neuropilin (NP) signal plays critical roles for breast cancer stem cells. We sorted NP-positive and control NP-negative cell population derived from breast cancer patient samples and analyzed transcriptome at single cell levels by using the cutting-edge technologies. We found that NP-positive cell population show strong variance in mRNA expression patterns than NP-negative cell population. These findings suggest that NP-positive cells are composed of more heterogenous cell populations with clear hierarchy than NP-negative cells.

Research Products

• [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: 108 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] ddiction 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
• [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
  • DOI: 10.18632/oncotarget.15276
  • 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 EI, Yano M, Sugano S, Shimono Y, Ishii H, Saya H, Mori M, Akashi K, Tada KI, Ogawa T, Tojo A, Miyano S, Gotoh N
  • Journal Title: Oncogene. Volume: 36(9) Pages: 1276-1286
  • DOI: 10.1038/onc.2016.293
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Oncogenic fusion gene CD74-NRG1 confers cancer stem cell-like properties in lung cancer through a IGF2 autocrine/paracrine circuit. (2016)
  • Author(s): Murayama T, Nakaoku T, Enari T, Nishimura T, Tominaga K, Nakata A, Tojo A, Sugano S, Kohno T, Gotoh N.
  • Journal Title: Cancer Res. Volume: 76 Pages: 974-983
  • NAID: 120005741610
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Oncogenic Fusion Gene CD74-NRG1 Confers Cancer Stem Cell-like Properties in Lung Cancer through a IGF2 Autocrine/Paracrine Circuit. (2016)
  • Author(s): Murayama T, Nakaoku T, Enari T, Nishimura T, Tominaga K, Nakata A, Tojo A, Sugano S, Kohno T, Gotoh N.
  • Journal Title: Cancer Research Volume: 76 Pages: 974-83
  • DOI: 10.1158/0008-5472.can-15-2135
  • NAID: 120005741610
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Elevated beta-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs. (2015)
  • Author(s): Nakata A, Yoshida R, Yamaguchi R, Yamauchi M, Tamada Y, Fujita A, Shimamura T, Imoto S, Higuchi T, Nomura M, Kimura T, Nokihara H, Higashiyama M, Kondoh K, Nishihara H, Tojo A, Yano S, Miyano S, Gotoh N
  • Journal Title: Scientific Reports Volume: 5 Pages: 13076-13076
  • DOI: 10.1038/srep13076
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A novel serum 4-microRNA signature for lung cancer detection. (2015)
  • Author(s): Nadal E, Truini A, Nakata A, Lin J, Reddy RM, Chang AC, Ramnath N, Gotoh N, Beer DG, Chen G.
  • Journal Title: Scientific Reports Volume: 5 Pages: 12464-12464
  • DOI: 10.1038/srep12464
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Embryonic MicroRNA-369 Controls Metabolic Splicing Factors and Urges Cellular Reprograming. (2015)
  • Author(s): Masamitsu Konno, Jun Koseki, Koichi Kawamoto, Naohiro Nishida, Hidetoshi Matsui, Dyah Laksmi Dewi, Miyuki Ozaki, Yuko Noguchi, Koshi Mimori, Noriko Gotoh, Nobuhiro Tanuma, Hiroshi Shima, Yuichiro Doki, Masaki Mori , Hideshi Ishii
  • Journal Title: PLoS One Volume: 10(7) Pages: 1-16
  • DOI: 10.1371/journal.pone.0132789
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MicroRNAs Induce Epigenetic Reprogramming and Suppress Malignant Phenotypes of Human Colon Cancer Cells. (2015)
  • Author(s): Ogawa, H., Wu, X., Kawamoto, K., Nishida, N., Konno, M., Koseki, J., Matsui, H., Noguchi, K., Gotoh, N., Yamamoto, T., Miyata, K., Nishiyama, N., Nagano, H., Yamamoto, H., Obika, S., Kataoka, K., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: PLoS One Volume: 10 Pages: 1-23
  • DOI: 10.1371/journal.pone.0127119
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pyruvate Kinase M2, but not M1, allele maintains immature metabolic states of murine embryonic stem cells. (2015)
  • Author(s): Konno, M., Ishii, H., Koseki, J., Tanuma, N., Nishida, N., Kawamoto, K., Nishimura, T., Nakata, A., Matsui, H., Noguchi, K., Ozaki, M., Noguchi, Y., Shima, H., Gotoh N., Nagano, H., Doki, Y. and Mori, M.
  • Journal Title: Regenerative Therapy, Volume: 1 Pages: 63-71
  • DOI: 10.1016/j.reth.2015.01.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cyclin G2: A novel independent prognostic marker in pancreatic cancer. (2015)
  • Author(s): Hasegawa S, Nagano H, Konno M, Eguchi H, Tomokuni A, Tomimaru Y, Wada H, Hama N, Kawamoto K, Kobayashi S, Marubashi S, Nishida N, Koseki J, Gotoh N, Ohno S, Yabuta N, Nojima H, Mori M, Doki Y, Ishii H.
  • Journal Title: Oncology Letters Volume: 10 Pages: 2986-2990
  • DOI: 10.3892/ol.2015.3667
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Cancer stem-like cells derived from breast cancer or lung cancer. (2017)
  • Author(s): 後藤典子
  • Organizer: 第33回日本毒性病理学会総会
  • Place of Presentation: 大阪、ビッグ・アイ（国際障害者支援センター）
  • Year and Date: 2017-01-27
  • Invited
• [Presentation] セリン・グリシン代謝経路MTHFD2による肺がん幹細胞の維持 (2017)
  • Author(s): 後藤典子
  • Organizer: 第12回分子標的治療学会 TRワークショップ
  • Place of Presentation: 東京、都市センターホテル・コスモスホール
  • Year and Date: 2017-01-17
  • 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] 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
• [Presentation] Dependence on the mitochondrial MTHFD2-mediated purine synthetic pathway in lung cancer. (2016)
  • Author(s): 後藤典子
  • Organizer: 第39回日本分子生物学会年会シンポジウム
  • Place of Presentation: 横浜、パシフィコ横浜
  • Year and Date: 2016-12-02
  • Invited
• [Presentation] Growth factor signaling in cancer stem-like cells and their niche. The 47th International Symposium of the Princess Takamatsu Cancer Research Fund (2016)
  • Author(s): Gotoh Noriko.
  • Organizer: Current Status and Perspective of Cancer Stem Cell Research
  • Place of Presentation: 東京、パレスホテル東京
  • Year and Date: 2016-11-10
  • Invited
• [Presentation] セリン・グリシン代謝経路MTHFD2による肺がん幹細胞の維持 (2016)
  • Author(s): 後藤典子
  • Organizer: 第10回メタボロームシンポジウム：疾患マルチオミクス
  • Place of Presentation: 山形、鶴岡メタボロームキャンパス・レクチャーホール
  • Year and Date: 2016-10-21
  • Invited
• [Presentation] Oncogenic fusion gene CD74-NRG1 confers cancer stem cell-like properties in lung cancer through a IGF2 autocrine/paracrine circuit. (2016)
  • Author(s): Gotoh Noriko.
  • Organizer: The international academic seminar of tumor basis and clinical translational medicine in Jinan university
  • Place of Presentation: 中国、広州
  • Year and Date: 2016-10-12
  • Invited
• [Presentation] A serine-glycine metabolic enzyme MTHFD2 is a novel molecular target for overcoming resistance in lung cancer. (2016)
  • Author(s): 後藤典子
  • Organizer: 第75回日本癌学会学術総会シンポジウム：「代謝を標的としたがんの制御」
  • Place of Presentation: 横浜、パシフィコ横浜
  • Year and Date: 2016-10-06
  • Invited
• [Presentation] Novel therapeutic strategies to eradicate tumors by targeting cancer stem-like cells. (2016)
  • Author(s): 後藤典子
  • Organizer: 第14回日本臨床腫瘍学会学術集会シンポジウム：日本癌学会・日本臨床腫瘍学会合同シンポジウム
  • Place of Presentation: 神戸、神戸国際展示場、神戸国際会議場
  • Year and Date: 2016-07-29
  • Invited
• [Presentation] グリシン-セリン代謝経路の創薬標的MTHFD2 (2016)
  • Author(s): 後藤典子
  • Organizer: 第4回がんと代謝研究会セッション9：創薬
  • Place of Presentation: 鹿児島、かごしま県民交流センター
  • Year and Date: 2016-07-08
  • Invited
• [Presentation] がん幹細胞を標的とするがん根治療法戦略 (2016)
  • Author(s): 後藤典子
  • Organizer: 第15回新規素材探索研究会：特別講演
  • Place of Presentation: 横浜、新横浜フジビューホテル
  • Year and Date: 2016-06-03
  • Invited
• [Presentation] 乳がん、肺がんのがん幹細胞様細胞の分子標的. (2016)
  • Author(s): 後藤典子
  • Organizer: 第20回日本がん分子標的治療学会学術集会ワークショップ：がん幹細胞を標的にした治療
  • Place of Presentation: 大分、別府国際コンベンションセンター
  • Year and Date: 2016-06-01
  • Invited
• [Presentation] Stem cells, progenitor cells and cancer stem cells in breast tissues. (2016)
  • Author(s): 後藤典子
  • Organizer: 第89回日本内分泌学会総会シンポジウム「内分泌器官の組織幹細胞と腫瘍幹細胞」
  • Place of Presentation: 京都府、国立京都国際会館
  • Year and Date: 2016-04-22
  • Invited
• [Presentation] Molecular targets in the signaling and metabolism in cancer stem cells and their niche (2015)
  • Author(s): 後藤典子
  • Organizer: 第38回日本分子生物学会年会第88回日本生化学会大会・合同大会ワークショップ「がん治療抵抗性にむけた新しいアプローチ」
  • Place of Presentation: 神戸ポートアイランド、神戸市
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] CD74-NRG1, an oncogenic fusion gene product, leads to insulin-like growth factor 2 autocrine/paracrine circuit and confers cancer stem cell properties (2015)
  • Author(s): 後藤典子
  • Organizer: The 20th Korea-Japan Cancer Research Workshop
  • Place of Presentation: ロイヤルパークホテル ザ 汐留、東京都
  • Year and Date: 2015-11-30
  • Int'l Joint Research / Invited
• [Presentation] 増殖因子によるシグナル制御から得られた耐性克服のための新規分子標的 (2015)
  • Author(s): 後藤典子
  • Organizer: 第56回日本肺癌学会学術集会シンポジウム・「肺癌のトランスレーショナルリサーチ（分子標的薬の耐性克服）」
  • Place of Presentation: パシフィコ横浜、横浜市
  • Year and Date: 2015-11-27
  • Invited
• [Presentation] がん幹細胞―乳がんの癌幹細胞研究と臨床応用への展望 (2015)
  • Author(s): 後藤典子
  • Organizer: 第53回日本癌治療学会・日本癌学会合同シンポジウム：がん治療のゲノム個別化Precision Medicineを目指す多様な視点
  • Place of Presentation: 国立京都国際会館・グランドプリンスホテル京都、京都市
  • Year and Date: 2015-10-30
  • Invited
• [Presentation] Molecular targets in the signaling and metabolism in cancer stem cells and their niche (2015)
  • Author(s): 後藤典子
  • Organizer: 第74回日本癌学会学術総会特別シンポジウム「女性研究者による癌研究」
  • Place of Presentation: 名古屋国際会議場、名古屋市
  • Year and Date: 2015-10-09
  • Invited
• [Presentation] MICAL3 regulates stemness of human breast cancer (2015)
  • Author(s): 後藤典子
  • Organizer: 第13回日本臨床腫瘍学会学術集会シンポジウム「がん幹細胞の分子標的・免疫制御の新展開
  • Place of Presentation: ロイトン札幌・ホテルさっぽろ芸文館、札幌市
  • Year and Date: 2015-07-16
  • Invited
• [Presentation] Maintenance of stemness of breast cancer stem-like cells by FRS2beta, a feedback inhibitor for HER, during mammary tumorigenesis. (2015)
  • Author(s): 後藤典子
  • Organizer: 2015 SNUCRI Cancer Sympotisum
  • Place of Presentation: クムホ ファスン リゾート 光州、韓国
  • Year and Date: 2015-04-03
  • Int'l Joint Research / Invited