Identification of lingual and esophageal epithelial stem cells and their hierarchy, and of target genes for cancer treatment

• Project/Area Number: 15H02364
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kansai Medical University
• Principal Investigator: UENO Hiroo 関西医科大学, 医学部, 教授 (60332368)
• Co-Investigator(Kenkyū-buntansha): 厚海 奈穂 関西医科大学, 医学部, 助教 (90612151)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥42,900,000 (Direct Cost: ¥33,000,000、Indirect Cost: ¥9,900,000); Fiscal Year 2017: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000); Fiscal Year 2016: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000); Fiscal Year 2015: ¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
• Keywords: 幹細胞 / 癌 / 発生、分化 / 成体幹細胞 / がん幹細胞

Outline of Final Research Achievements

It has been proposed by Doupe et al (2012 Science) that the specific adult stem cells do not exist in the esophageal epithelial tissue. We by the multicolor cell lineage tracing method found that the gene A positive esophageal epithelial basal cells include esophageal epithelial stem cells. Also, by single cell RNAseq method of isolated esophageal epithelial tissue, and cell clustering based on the expressed genes, we identified a group of esophageal epithelial stem cells, and specific markers for them.

Academic Significance and Societal Importance of the Research Achievements

本研究により、これまでその存在さえ明らかでなかった食道上皮幹細胞の詳細が明らかとなった。また、化学発がんモデルを用いてがん化した組織より当該幹細胞に相当する細胞集団（がん幹細胞候補細胞）とのsingle cell RNAseqの比較検討を行い、その差異を解析を通じて、これまで決め手となる分子標的療法にかけていた食道がんの新規分子標的療法開発への基盤が形成できた。

Research Products

• [Journal Article] Intestinal stem cells contribute to the maturation of the neonatal small intestine and colon independently of digestive activity. (2017)
  • Author(s): Yanai H, Atsumi N, Tanaka T, Nakamura N, Komai Y, Omachi T, Tanaka K, Ishigaki K, Saiga K, Ohsugi H, Tokuyama Y, Imahashi Y, Ohe S, Hisha H, Yoshida N, Kumano K, Kon M, Ueno H.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 9891-9901
  • DOI: 10.1038/s41598-017-09927-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal (2017)
  • Author(s): Yan KS, Janda CY, Chang J, Zheng GXY, Larkin KA, Luca VC, Chia LA, Mah AT, Han A, Terry JM, Ootani A, Roelf K, Lee M, Yuan J, Li X, Bolen CR, Wilhelmy J, DaviesPS, Ueno H, von Furstenberg RJ, Belgrader P, Ziraldo SB, Ordonez H, Henning SJ, Wong MH, Snyder MP, Weissman IL, Hsueh AJ, Mikkelsen TS, Garcia KC, and Kuo CJ.
  • Journal Title: Nature Volume: 545 Issue: 7653 Pages: 238-242
  • DOI: 10.1038/nature22313
  • Peer Reviewed / Open Access
• [Journal Article] Identification of mouse cochlear progenitors that develop hair and supporting cells in the organ of Corti (2017)
  • Author(s): Xu Jinshu、Ueno Hiroo、Xu Chelsea Y.、Chen Binglai、Weissman Irving L.、Xu Pin-Xian
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 15046-15046
  • DOI: 10.1038/ncomms15046
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal cancer stem cells marked by Bmi1 or Lgr5 expression contribute to tumor propagation via clonal expansion. (2017)
  • Author(s): Hirotsugu Yanai, Naho Atsumi, Toshihiro Tanaka, Naohiro Nakamura, Yoshihiro Komai, Taichi Omachi, Kiyomichi Tanaka, Kazuhiko Ishigaki, Kazuho Saiga, Haruyuki Ohsugi, Yoko Tokuyama, Yuki Imahashi, Shuichi Ohe, Hiroko Hisha, Naoko Yoshida, Keiki Kumano, Masanori Kon and Ueno H.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 41838-41847
  • DOI: 10.1038/srep41838
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of mouse cochlear progenitors that develop hair and supporting cells in the organ of Corti. (2017)
  • Author(s): Jinshu Xu, H Ueno ,Chelsea Xu, Binglai Chen, Irving Weissman, and Pin-Xian Xu
  • Journal Title: Nature Communications Volume: -
  • Int'l Joint Research
• [Journal Article] Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem cell self-renewal (2017)
  • Author(s): KS Yan, CY Janda, J Chang, GXY Zheng, KA Larkin, VC Luca, LA Chia, AT Mah, A Han, JM Terry, A Ootani, K Roelf, M Lee, J Yuan, X Li, CR Bolen,J Wilhelmy, PS Davies, H Ueno , RJ von Furstenberg, P Belgrader, SB Ziraldo, H Ordonez, SJ Henning, MH Wong, MP Snyder, IL Weissman, AJ Hsueh, TS Mikkelsen, KC Garcia, and CJ Kuo
  • Journal Title: Nature Volume: -
  • Int'l Joint Research
• [Journal Article] Identification of normal and neoplastic stem cells by the multicolor lineage tracing method. (2016)
  • Author(s): Ueno H
  • Journal Title: Pathology International Volume: 66 Issue: 8 Pages: 423-430
  • DOI: 10.1111/pin.12425
  • Peer Reviewed
• [Journal Article] Bmi1-positive cells in the lingual epithelium could serve as cancer stem cells in tongue cancer (2016)
  • Author(s): T Tanaka, N Atsumi, N Nakamura, H Yanai, Y Komai, T Omachi, K Tanaka, K Ishigaki, K Saiga, H Ohsugi, Y Tokuyama, Y Imahashi, H Hisha, N Yoshida, K Kumano, K Okazaki, and Ueno H
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 39386-39391
  • DOI: 10.1038/srep39386
  • Peer Reviewed / Open Access
• [Journal Article] Intracellular signals of lung cancer cells as possible therapeutic targets. (2015)
  • Author(s): Tanaka K, Kumano K, Ueno H
  • Journal Title: Cancer Science Volume: 未定 Issue: 5 Pages: 489-496
  • DOI: 10.1111/cas.12643
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Maintenance of sweat glands by stem cells located in the acral epithelium. (2015)
  • Author(s): Ohe S, Tanaka T, Yanai H, Komai Y, Omachi T, Kanno S, Tanaka K, Ishigaki K, Saiga K, Nakamura N, Ohsugi H, Tokuyama Y, Atsumi N, Hisha H, Yoshida N, Kumano K, Yamazaki F, Okamoto H, Ueno H
  • Journal Title: Biochemical and biophysical research communications Volume: 466 Pages: 333-338
  • Peer Reviewed
• [Presentation] 多色細胞系譜追跡法を用いた成体幹細胞同定-耳鼻咽頭科領域の成体幹細胞とそのがん化について (2017)
  • Author(s): 上野博夫
  • Organizer: 第35回耳鼻咽喉科ニューロサイエンス研究会
  • Invited
• [Presentation] 多色細胞系譜追跡法を用いた成体幹細胞研究 (2017)
  • Author(s): 上野博夫
  • Organizer: 京都大学ウィルス・再生医学研究所 第1回 個体の中の細胞社会学セミナー
  • Invited
• [Presentation] 多色細胞系譜追跡法とシングル・セルRNAseqの融合による成体幹細胞同定 (2017)
  • Author(s): 上野博夫
  • Organizer: 第17回日本再生医療学会総会
  • Invited
• [Presentation] organoids of tongue and esophagus (2016)
  • Author(s): 上野博夫
  • Organizer: EMBO|EMBL Symposium
  • Place of Presentation: ドイツ ハイデルベルク
  • Year and Date: 2016-10-12
  • Int'l Joint Research
• [Presentation] 多色細胞系譜追跡法による新規成体幹細胞、がん幹細胞の同定 (2016)
  • Author(s): 上野博夫
  • Organizer: 第25回日本形成外科学会基礎学術集会
  • Place of Presentation: 大阪 ナレッジキャピタル コングレ・コンベンションセンター
  • Year and Date: 2016-09-15
  • Invited
• [Presentation] Identification of novel stem cells by the multicolor lineage tracing method (2015)
  • Author(s): 上野博夫
  • Organizer: BMB2015(第38回日本分子生物学会年会 第88回日本生化学大会 合同大会)
  • Place of Presentation: 神戸 神戸ポートアイランド
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] Indentification of normal and cancer stem cells and their niche (2015)
  • Author(s): 上野博夫
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋 名古屋国際会議場
  • Year and Date: 2015-10-08
  • Invited
• [Presentation] 多色細胞系譜追跡法による成体幹細胞・がん幹細胞の解析 (2015)
  • Author(s): 上野博夫
  • Organizer: 平成27年度「がん研究分野の特性等を踏まえた支援活動」支援説明会・公開シンポジウム
  • Place of Presentation: 東京 一橋講堂 学術総合センター
  • Year and Date: 2015-09-09
  • Invited
• [Presentation] 多色細胞系譜追跡による成体幹細胞の同定・発生・がん化研究 (2015)
  • Author(s): 上野博夫
  • Organizer: 関西眼科先進医療研究会
  • Place of Presentation: 大阪 大阪大学
  • Year and Date: 2015-07-01
  • Invited
• [Presentation] 新規成体幹細胞の同定とがん化における細胞動態解析 (2015)
  • Author(s): 上野博夫
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋 名古屋国際会議場
  • Year and Date: 2015-04-30
  • Invited
• [Remarks] 関西医科大学実験病理学講座
  • URL: http://www3.kmu.ac.jp/pathol1/index.html
• [Patent(Industrial Property Rights)] 舌上皮幹細胞及び舌上皮幹細胞に由来する細胞塊 (2017)
  • Inventor(s): 上野博夫
  • Industrial Property Rights Holder: 上野博夫
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017