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: National Cancer Center Japan (2020); Hiroshima University (2018-2019)
• Principal Investigator: Naoya Sakamoto 国立研究開発法人国立がん研究センター, 先端医療開発センター, ユニット長 (20571798)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• 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: 胃癌 / オルガノイド / 幹細胞 / 胃がん

Outline of Final Research Achievements

Gastric cancer (GC) is generally sub-classified into "intestinal type" that expresses MUC2 or CD10 and "gastric type" that expresses MUC5AC or MUC6 based on the immunohistochemical analysis. It is well known that both intestinal and gastric type cancers are underpinned by different genetic and molecular background.
We generated a GC organoid library that is composed of 50 GC cases, including the results of several IHC staining, MSI and mutation status. We also examined the drug sensitivity against representative anti-cancer drugs.
We then performed RNA sequence using GC organoids with intestinal and gastric types, and found out several candidate genes that are involved in the resistance against 5-FU and oxaliplatin. Currently, several studies that aim to reveal molecular machinery concerning attainment of drug resistance are ongoing. We are also conducting a screening of the specific inhibitors against above-mentioned candidates in collaboration with a pharmatheutic company.

Academic Significance and Societal Importance of the Research Achievements

オルガノイドは幹細胞を豊富に含んでおり、胃癌オルガノイドは癌幹細胞を豊富に含んでいると考えられることから、今回同定した候補遺伝子は癌幹細胞を標的とした治療につながる可能性が考えられる。
胃癌オルガノイドを用いた研究はこれまでになく、非常に新規性の高い研究であると考えられ、根治を目指した癌幹細胞を標的とした治療開発に加えて、胃型、腸型胃癌の病態形成のメカニズムなど、様々な新知見をもたらすものと期待される。

Research Products

• [Journal Article] KHDRBS3 promotes multi-drug resistance and anchorage-independent growth in colorectal cancer. (2021)
  • Author(s): Ukai S, Sakamoto N, Taniyama D, Harada K, Honma R, Maruyama R, Naka K, Hinoi T, Takakura Y, Shimizu W, Ohdan H, Yasui W
  • Journal Title: Cancer Science Volume: 112 Pages: 1196-1208
  • DOI: 10.1111/cas.14805
  • Peer Reviewed / Open Access
• [Journal Article] BUB1B Overexpression Is an Independent Prognostic Marker and Associated with CD44, p53, and PD-L1 in Renal Cell Carcinoma. (2021)
  • Author(s): Sekino Y, Han X, Kobayashi G, Babasaki T, Miyamoto S, Kobatake K, Kitano H, Ikeda K, Goto K, Inoue S, Hayashi T, Teishima J, Sakamoto N, Sentani K, Oue N, Yasui W, Matsubara A
  • Journal Title: Oncology Volume: - Pages: 240-250
  • DOI: 10.1159/000512446
  • Peer Reviewed / Open Access
• [Journal Article] Microtubule-associated protein tau (MAPT) is a promising independent prognostic marker and tumor suppressive protein in clear cell renal cell carcinoma. (2020)
  • Author(s): Han X, Sekino Y, Babasaki T, Goto K, Inoue S, Hayashi T, Teishima J, Sakamoto N, Sentani K, Oue N, Yasui W, Matsubara A.
  • Journal Title: Urol Oncol Volume: - Pages: 9-17
  • DOI: 10.1016/j.urolonc.2020.02.010
  • Peer Reviewed / Open Access
• [Journal Article] UC-63+ contributes to gastric cancer progression through regulation of NF-κB signaling (2020)
  • Author(s): Sakamoto N, Sekino Y, Fukada, Pham QT, Honma R, Taniyama D, Ukai S, Takashima T, Hattori T, Naka K, Tanabe K, Ohdan H, Yasui W
  • Journal Title: Gastric Cancer Volume: 23 Pages: 863873-863873
  • DOI: 10.1007/s10120-020-01070-8
  • Peer Reviewed / Open Access
• [Journal Article] Immunohistochemical analysis of SLFN11 expression uncovers potential non-responders to DNA-damaging agents overlooked by tissue RNA-seq (2020)
  • Author(s): Takashima Tsuyoshi、Sakamoto Naoya、Murai Junko、Taniyama Daiki、Honma Ririno、Ukai Shoichi、Maruyama Ryota、Kuraoka Kazuya、Rajapakse Vinodh N.、Pommier Yves、Yasui Wataru
  • Journal Title: Virchows Archives Volume: 478 Pages: 569-579
  • DOI: 10.1007/s00428-020-02840-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] SPC18 Expression Is an Independent Prognostic Indicator of Patients with Esophageal Squamous Cell Carcinoma (2020)
  • Author(s): Yamamoto Yuji、Oue Naohide、Asai Ryuichi、Katsuya Narutaka、Uraoka Naohiro、Sakamoto Naoya、Sentani Kazuhiro、Tanabe Kazuaki、Ohdan Hideki、Yasui Wataru
  • Journal Title: Pathobiol Volume: 87 Pages: 254-261
  • DOI: 10.1159/000506956
  • Peer Reviewed / Open Access
• [Journal Article] TUBB3 Is Associated with High-Grade Histology, Poor Prognosis, p53 Expression, and Cancer Stem Cell Markers in Clear Cell Renal Cell Carcinoma (2020)
  • Author(s): Sekino Yohei、Han Xiangrui、Babasaki Takashi、Miyamoto Shunsuke、Kitano Hiroyuki、Kobayashi Go、Goto Keisuke、Inoue Shogo、Hayashi Tetsutaro、Teishima Jun、Sakamoto Naoya、Sentani Kazuhiro、Oue Naohide、Yasui Wataru、Matsubara Akio
  • Journal Title: Oncology Volume: 98 Pages: 689-698
  • DOI: 10.1159/000506775
  • Peer Reviewed / Open Access
• [Journal Article] Oncogenic mutation in RAS‐RAF axis leads to increased expression of GREB1, resulting in tumor proliferation in colorectal cancer (2020)
  • Author(s): Kochi Masatoshi、Hinoi Takao、Niitsu Hiroaki、Miguchi Masashi、Saito Yasufumi、Sada Haruki、Sentani Kazuhiro、Sakamoto Naoya、Oue Naohide、Tashiro Hirotaka、Sotomaru Yusuke、Yasui Wataru、Ohdan Hideki
  • Journal Title: Cancer Sci Volume: 111 Pages: 3540-3549
  • DOI: 10.1111/cas.14558
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular biological analysis of 5-FU-resistant gastric cancer organoids; KHDRBS3 contributes to the attainment of features of cancer stem cell (2020)
  • Author(s): Ukai S, Honma R, Sakamoto N, Yamamoto Y, Pham QT, Harada K, Takashima T, Taniyama D, Asai R, Fukada K, Naka K, Tanabe K, Ohdan K, Yasui W
  • Journal Title: Oncogene Volume: 39 Pages: 7265-7278
  • DOI: 10.1038/s41388-020-01492-9
  • Peer Reviewed / Open Access
• [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: Oncology Reports 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] 5-FU 耐性胃がんオルガノイドを用いたメタボローム解析 (2020)
  • Author(s): 坂本直也、仲 一仁、鵜飼翔一、本間りりの、谷山大樹、高島剛志、仙谷和弘、大上直秀、安井 弥
  • Organizer: 第109回日本病理学会総会
• [Presentation] 5-FU耐性胃癌オルガノイドの樹立およびその機能解析 (2020)
  • Author(s): 鵜飼翔一、坂本直也、本間りりの、谷山大樹、高島剛志、仙谷和弘、大上直秀、安井 弥
  • Organizer: 第109回日本病理学会総会
• [Presentation] 消化管癌オルガノイドを用いたトリフルリジンの効用の検討 (2020)
  • Author(s): 丸山諒太、坂本直也、谷山大樹、本間りりの、鵜飼翔一、仙谷和弘、大上直秀、安井 弥
  • Organizer: 第109回日本病理学会総会
• [Presentation] オキサリプラチン耐性胃がんオルガノイドの樹立及びその機能解析 (2020)
  • Author(s): 原田健司、坂本直也、鵜飼翔一、高島剛志、丸山諒太、本間りりの、谷山大樹、仙谷和弘、大上直秀、安井 弥
  • Organizer: 第109回日本病理学会総会
• [Presentation] 尿路上皮癌におけるSLFN11とDNA障害型抗がん剤の相関 (2020)
  • Author(s): 谷山大樹、坂本直也、村井純子、高島剛志、林哲太郎、仙谷和弘、大上直秀、安井 弥
  • Organizer: 第109回日本病理学会総会
• [Presentation] 尿路上皮癌におけるSLFN11とDNA障害型抗がん剤の効果の関連 (2020)
  • Author(s): 谷山大樹、坂本直也、村井純子、高島 剛、林哲太郎、亭島 淳、松原昭郎、安井 弥
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 5-FU耐性胃癌オルガノイドの樹立とその癌遺伝子学的解析 (2020)
  • Author(s): 鵜飼翔一、坂本直也、本間りりの、谷山大樹、Quoc Thang Pham、高島剛志、原田健司、仲 一仁、田邊和照、大段秀樹、安井 弥
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] オキサリプラチン耐性胃がんオルガノイドの樹立及びその機能的解析 (2020)
  • Author(s): 原田健司、坂本直也、鵜飼翔一、Quoc Thang Pham、高島剛志、丸山諒太、本間りりの、谷山大樹、田邊和照、大段秀樹、安井 弥
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 大腸癌オルガノイドを用いたトリフルリジン効用の検討 (2020)
  • Author(s): 丸山諒太、坂本直也、谷山大樹、常國健太、本間りりの、鵜飼翔一、檜井孝夫、大段秀樹、安井 弥
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 大腸癌の分子学的特徴と実験モデル (2020)
  • Author(s): 坂本直也、安井 弥
  • Organizer: 第79回日本癌学会学術総会
  • Invited
• [Presentation] Metabolome analysis using 5-FU resistant gastric cancer organoids (2020)
  • Author(s): Naoya Sakamoto, Kazuhito Naka, Shoichi Ukai, Daiki Taniyama, Atsushi Ochiai, Wataru Yasui
  • Organizer: 第31回消化器癌発生学会総会
• [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