Search for new therapeutic target against cancer stem cells using intestinal-/gastric type gastric cancer organoid

• Project/Area Number: 18K07017
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Hiroshima University
• Principal Investigator: 坂本 直也 広島大学, 医系科学研究科(医), 助教 (20571798)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Granted (Fiscal Year 2019)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: オルガノイド / 胃がん

Outline of Annual Research Achievements

胃がんは免疫組織学的な粘液発現のパターンにより、MUC2もしくはCD10陽性の腸型胃がん、MUC5ACもしくはMUC6陽性の胃型胃がんに大別される。腸型・胃型胃
がんでは、背景に存在する遺伝子・分子異常を含めたpathogenesisが大きく異なることが知られている。
本研究では、外科的切除材料から、胃がん組織及び非腫瘍部胃粘膜を採取し、いずれのサンプルも二分して、胃もしくは小腸/結腸オルガノイド培養のmediumを用い、腸型・胃型胃がんオルガノイドもしくは正常胃粘膜/腸上皮化生オルガノイドを樹立した。各々のオルガノイドに関して、MUC2/CD10/MUC5AC/MUC6の免疫染色やPAS/Alcian Blueの特殊染色を行い、その特性を確認した。現在までに50例の胃癌オルガノイドの樹立に成功しており、内訳としては胃型:17例、腸型:15例、胃腸混合型:18例、分類不能型:3例であった。
樹立した胃癌オルガノイドを用いて、p53、MLH1、β-cateninの免疫染色や、MSI解析、TP53、KRAS、RHOA、TGFBR2、ARID1、ACVR2Aの遺伝子変異解析を行い、全ての情報を含めたライブラリー構築を進めている。
加えて、胃がんの化学療法に用いられる代表的な薬剤 (5-FU、オキサリプラチン)に対する薬剤感受性の検討も進めており、現在37例において5-FU、オキサリプラチンのIC50値の測定を終えた。
現在オルガノイドサンプルを用いたRNA sequencing解析による遺伝子発現プロファイルの解析中である。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

オルガノイドの樹立、薬剤感受性の解析まで順調に終了している

Strategy for Future Research Activity

現在胃型胃がん5例、腸型胃がん5例に関して、RNA sequencingの解析を依頼しており、結果を待っている状態である。薬剤感受性、表現型の結果も含めて、発現プロファイルの解析を行い、薬剤耐性マーカーの絞り込みを行う。

Research Products

• [Journal Article] Annexin A10 Is Involved in the Induction of Pancreatic Duodenal homeobox in Gastric Cancer Tissue, Cells and Organoids (2020)
  • Author(s): Ishikawa A, Sakamoto N, Honma R, Taniyama D, Fukada K, Hattori T, Sentani K, Oue N, Yanagihara K, Tanabe K, Ohdan H, Yasui W.
  • Journal Title: Oncol Rep. Volume: 43 Pages: 581-590
  • DOI: 10.3892/or.2019.7422
  • Peer Reviewed
• [Journal Article] Molecular Carcinogenesis of Gastric Cancer: Lauren Classification, Mucin Phenotype Expression, and Cancer Stem Cells (2019)
  • Author(s): Oue N, Sentani K, Sakamoto N, Uraoka N, Yasui W.
  • Journal Title: Int J Clin Oncol. Volume: 印刷中 Pages: 771-778
  • DOI: 10.1007/s10147-019-01443-9
  • Peer Reviewed
• [Journal Article] Cancer Extracellular Vesicles Contribute to Stromal Heterogeneity by Inducing Chemokines in Cancer-Associated Fibroblasts (2019)
  • Author(s): Naito Y, Yamamoto Y, Sakamoto N, Shimomura I, Kogure A, Kumazaki M, Yokoi A, Yashiro M, Kiyono T, Yanagihara K, Takahashi RU, Hirakawa K, Yasui W, Ochiya T.
  • Journal Title: Oncogene. Volume: 38 Pages: 5566-5579
  • DOI: 10.1038/s41388-019-0832-4
  • Peer Reviewed / Open Access
• [Journal Article] SEC11A Expression Is Associated with Basal-Like Bladder Cancer and Predicts Patient Survival. (2019)
  • Author(s): Shigematsu Yoshinori、Oue Naohide、Sekino Yohei、Sakamoto Naoya、Sentani Kazuhiro、Uraoka Naohiro、Hayashi Tetsutaro、Teishima Jun、Matsubara Akio、Yasui Wataru
  • Journal Title: Pathobiology. Volume: 86 Pages: 208-216
  • DOI: 10.1159/000497206
  • Peer Reviewed / Open Access
• [Journal Article] CD204-Positive Tumor-associated Macrophages Relate to Malignant Transformation of Colorectal Adenoma (2019)
  • Author(s): TANIYAMA DAIKI、TANIYAMA KIYOMI、KURAOKA KAZUYA、YAMAMOTO HIDEKI、ZAITSU JUNICHI、SAITO AKIHISA、SAKAMOTO NAOYA、SENTANI KAZUHIRO、OUE NAOHIDE、YASUI WATARU
  • Journal Title: Anticancer Res Volume: 39 Pages: 2767-2775
  • DOI: 10.21873/anticanres.13403
  • Peer Reviewed
• [Journal Article] miR-130b Promotes Sunitinib Resistance through Regulation of PTEN in Renal Cell Carcinoma. (2019)
  • Author(s): Sekino Yohei、Sakamoto Naoya、Sentani Kazuhiro、Oue Naohide、Teishima Jun、Matsubara Akio、Yasui Wataru
  • Journal Title: Oncology. Volume: 97 Pages: 164-172
  • DOI: 10.1159/000500605
  • Peer Reviewed / Open Access
• [Journal Article] Synbiotics Suppress Colitis-Induced Tumorigenesis in a Colon-Specific Cancer Mouse Model (2019)
  • Author(s): Saito Y, Hinoi T, Adachi T, Miguchi M, Niitsu H, Kochi M, Sada H, Sotomaru Y, Sakamoto N, Sentani K, Oue N, Yasui W, Tashiro H, Ohdan H.
  • Journal Title: PLos One Volume: 14 Pages: 0216393-0216393
  • DOI: 10.1371/journal.pone.0216393
  • Peer Reviewed / Open Access
• [Journal Article] IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma (2019)
  • Author(s): Kofuji S, Hirayama A, Eberhardt AO, Kawaguchi R, Sakamoto N, Kitahara S, Wolfe K, Lange L, Onishi N, Uematsu M, Saya H, Soga T, Grummt I, Bierhoff H, Sasaki AT.
  • Journal Title: Nat Cell Biol. Volume: 21 Pages: 1003-1014
  • DOI: 10.1038/s41556-019-0363-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinicopathological significance of claspin overexpression and its association with spheroid formation in gastric cancer (2019)
  • Author(s): Kobayashi G, Sentani K, Hattori T, Yamamoto Y, Imai T, Sakamoto N, Kuraoka K, Oue N, Sasaki N, Taniyama K, Yasui W.
  • Journal Title: Human Pathology Volume: 84 Pages: 8-17
  • DOI: 10.1016/j.humpath.2018.09.001
  • Peer Reviewed
• [Journal Article] Uc.416+A promotes epithelial-to-mesenchymal transition through miR-153 in renal cell carcinoma. (2019)
  • Author(s): Sekino Yohei、Sakamoto Naoya、Goto Keisuke、Honma Ririno、Shigematsu Yoshinori、Quoc Thang Pham、Sentani Kazuhiro、Oue Naohide、Teishima Jun、Kawakami Fumi、Karam Jose A、Sircar Kanishka、Matsubara Akio、Yasui Wataru
  • Journal Title: BMC Cancer. Volume: 18 Pages: 952-952
  • DOI: 10.1186/s12885-018-4863-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinicopathological significance of RCAN2 production in gastric carcinoma. (2019)
  • Author(s): Hattori Y, Sentani K, Shinmei S, Oo HZ, Hattori T, Imai T, Sekino Y, Sakamoto N, Oue N, Niitsu H, Hinoi T, Ohdan H, Yasui W.
  • Journal Title: Histopathology. Volume: 74 Pages: 430-442
  • DOI: 10.1111/his.13764
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protocadherin B9 promotes resistance to bicalutamide and is associated with the survival of prostate cancer patients. (2019)
  • Author(s): Sekino Y, Oue N, Mukai S, Shigematsu Y, Goto K, Sakamoto N, Sentani K, Hayashi T, Teishima J, Matsubara A, Yasui W.
  • Journal Title: Prostate. Volume: 79 Pages: 234-242
  • DOI: 10.1002/pros.23728
  • Peer Reviewed / Open Access
• [Journal Article] KIFC1 Inhibitor CW069 Induces Apoptosis and Reverses Resistance to Docetaxel in Prostate Cancer (2019)
  • Author(s): Sekino Y, Oue N, Koike Y, Shigematsu Y, Sakamoto N, Sentani K, Teishima J, Shiota M, Matsubara A, Yasui W.
  • Journal Title: Journal of Clinical Medicine Volume: 8 Pages: 225-225
  • DOI: 10.3390/jcm8020225
  • Peer Reviewed / Open Access
• [Journal Article] Transcribed ultraconserved region Uc.63+ promotes resistance to cisplatin through regulation of androgen receptor signaling in bladder cancer. (2019)
  • Author(s): Sekino Y, Sakamoto N, Ishikawa A, Honma R, Shigematsu Y, Hayashi T, Sentani K, Oue N, Teishima J, Matsubara A, Yasui W.
  • Journal Title: Oncol Rep Volume: 41 Pages: 3111-3118
  • Peer Reviewed
• [Journal Article] Clinicopathological and Prognostic Significance of Epithelial Gremlin1 Expression in Gastric Cancer (2018)
  • Author(s): Honma R, Sakamoto N, Ishikawa A, Taniyama D, Fukada K, Hattori T, Sentani K, Oue N, Tanabe K, Ohdan H, Yasui W.
  • Journal Title: Anticancer Res Volume: 38 Pages: 1419-1425
  • Peer Reviewed
• [Journal Article] TDO2 Overexpression Is Associated with Cancer Stem Cells and Poor Prognosis in Esophageal Squamous Cell Carcinoma. (2018)
  • Author(s): Pham Quoc Thang、Oue Naohide、Sekino Yohei、Yamamoto Yuji、Shigematsu Yoshinori、Sakamoto Naoya、Sentani Kazuhiro、Uraoka Naohiro、Yasui Wataru
  • Journal Title: Oncology. Volume: 95 Pages: 297-308
  • DOI: 10.1159/000490725
  • Peer Reviewed / Int'l Joint Research
• [Presentation] オルガノイドを用いた癌幹細胞特異的な遺伝子・分子異常の解析. (2019)
  • Author(s): 坂本直也、本間りりの、鵜飼翔一、仙谷和弘、大上直秀、安井 弥
  • Organizer: 第108回日本病理学会総会、シンポジウム 5「オルガノイドとPDX」
  • Invited