Cancer stem cell purification and drug discovery support by the overall disease model using a new PDX model

• Project/Area Number: 18H02840
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Ehime University
• Principal Investigator: Takenaka Katsuto 愛媛大学, 医学系研究科, 教授 (30301295)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 患者腫瘍組織移植モデル / 免疫不全マウス / SIRPA / マクロファージ寛容 / がん幹細胞 / 患者組織移植モデル / ヒト疾患モデル

Outline of Final Research Achievements

The xenotransplantation system using immunodeficient mice, which was developed as an assay system for normal human hematopoietic stem cells, is a model for reproducing human diseases, such as stem cell purification and pathological elucidation of hematopoietic tumors and solid tumors, development of stem cell target therapy, and infection experiment model.We aimed to develop a next-generation patient-derived xenograft model that overcomes the problems of the current xenotransplantation system. In the B6 background, we introduced the Kit mutation for bone marrow niche opening and human SIPRA knock-in into Rag2 deficiency and IL2Rg deficiency, and established BRGhSK, which is the completed form of the next-generation PDX model.

Academic Significance and Societal Importance of the Research Achievements

本課題では、これまでの知見と実績をベースに全般的疾患再現モデルを構築可能な患者腫瘍組織移植モデルを開発し、腫瘍性幹細胞純化や創薬開発支援の基盤整備を行った。我々が注目する「SIRPA-CD47を介したマクロファージ寛容」は、異種移植の理論構築を新展開させた極めて独創的かつ有意義な発見であり、これをin vivo実験系に世界で初めて導入することにより、腫瘍性幹細胞の同定感度を飛躍的に上げることができる。本システムは、種々のPDXモデルに応用可能で、さらに、樹立された疾患モデルマウスは、ヒト細胞の薬剤感受性試験、再生医療や分子標的治療・遺伝子治療の前臨床試験などに応用可能である。

Research Products

• [Journal Article] A multicenter non-randomized, uncontrolled single arm trial for evaluation of the efficacy and the safety of the treatment with favipiravir for patients with severe fever with thrombocytopenia syndrome (2021)
  • Author(s): Suemori K, Saijo M, Yamanaka A, Himeji D, Kawamura M, Haku T, Hidaka M, Kamikokuryo C, Kakihana Y, Azuma T, Takenaka K, Takahashi T, Furumoto A, Ishimaru T, Ishida M, Kaneko M, Kadowaki N, Ikeda K, Sakabe S, Taniguchi T, Ohge H, Kurosu T, Yoshikawa T, Shimojima M, Yasukawa M.
  • Journal Title: PLOS Neglected Tropical Diseases Volume: 15
  • DOI: 10.1371/journal.pntd.0009103
  • Peer Reviewed / Open Access
• [Journal Article] Negative Impact of Cytomegalovirus Reactivation on Survival in Adult Patients with Aplastic Anemia after an Allogeneic Hematopoietic Stem Cell Transplantation: A Report from Transplantation-Related Complication and Adult Aplastic Anemia Working Groups of the Japan Society for Hematopoietic Cell Transplantation (2021)
  • Author(s): Takenaka Katsuto、Onishi Yasushi、Mori Takehiko、Hirakawa Tsuneaki、Tada Yuuma、Uchida Naoyuki、Kobayashi Takeshi、Kanda Yoshinobu、Ozawa Yukiyasu、Ota Shuichi、Iida Hiroatsu、Fukushima Kentaro、Kimua Takafumi、Fukuda Takahiro、Atsuta Yoshiko、Matsuto Keitaro、Yamazaki Hirohito、Nakasone Hideki
  • Journal Title: Transplantation and Cellular Therapy Volume: 27
  • DOI: 10.1016/j.bbmt.2020.10.001
  • Peer Reviewed
• [Journal Article] Efficacy of prophylactic letermovir for cytomegalovirus reactivation in hematopoietic cell transplantation: a multicenter real-world data (2020)
  • Author(s): Mori Yasuo, et al.
  • Journal Title: Bone Marrow Transplantation Volume: 56 Pages: 853-862
  • DOI: 10.1038/s41409-020-01082-z
  • Peer Reviewed
• [Journal Article] Cyclosporine/methotrexate versus tacrolimus/methotrexate with or without anti-thymocyte globulin as GVHD prophylaxis in adult patients with aplastic anemia (2020)
  • Author(s): Onishi Yasushi, et al.
  • Journal Title: Annals of Hematology Volume: 100 Pages: 217-228
  • DOI: 10.1007/s00277-020-04290-1
  • Peer Reviewed
• [Journal Article] Outcome of allogeneic hematopoietic stem cell transplantation in adult patients with paroxysmal nocturnal hemoglobinuria (2020)
  • Author(s): Nakamura Yukinori、Takenaka Katsuto、Yamazaki Hirohito、Onishi Yasushi、Ozawa Yukiyasu、Ikegame Kazuhiro、Matsuoka Ken-ichi、Toubai Tomomi、Ueda Yasunori、Kanda Yoshinobu、Ichinohe Tatsuo、Atsuta Yoshiko、Mori Takehiko
  • Journal Title: International Journal of Hematology Volume: 113 Pages: 122-127
  • DOI: 10.1007/s12185-020-02982-y
  • Peer Reviewed
• [Journal Article] TKIs induce alternative spliced BCR-ABLIns35bp variant via inhibition of RNA polymerase Ⅱ on genomic BCR-ABL. (2020)
  • Author(s): Yuda J, Odawara J, Minami M, Muta T, Kohno K, Tanimoto K, Eto T, Shima T, Kikushige Y, Kato K, Takenaka K, Iwasaki H, Minami Y, Ohkawa Y, Akashi K, Miyamoto T.
  • Journal Title: Cancer Science Volume: 111 Pages: 2361-2373
  • DOI: 10.1111/cas.14424
  • Peer Reviewed / Open Access
• [Journal Article] Favorable Effect of Cytomegalovirus Reactivation on Outcomes in Cord Blood Transplant and Its Differences Among Disease Risk or Type (2020)
  • Author(s): Yokoyama Hisayuki, et al.
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 26 Pages: 1363-1370
  • DOI: 10.1016/j.bbmt.2020.04.002
  • Peer Reviewed
• [Journal Article] Establishment of a human SIRPA knock-in xenograft mouse model to study human hematopoietic and cancer stem cells. (2020)
  • Author(s): Jinnouchi F, Yamauchi T, Yurino A, Nunomura T, Nakano M, Iwamoto C, Obara T, Miyawaki K, Kikushige Y, Kato K, Maeda T, Miyamoto T, Baba E, Akashi K, Takenaka K.
  • Journal Title: Blood Volume: - Pages: 1661-1672
  • DOI: 10.1182/blood.2019002194
  • Peer Reviewed / Open Access
• [Journal Article] Direct comparisoin of target-reactivity and cross-reactivity induced by CAR-and BiTE-redirected T cells for the development of antibody-based T-cell therapy. (2019)
  • Author(s): Masaki Maruta, Toshiki Ochi, Kazushi Tanimoto, Hiroaki Asai, et al.
  • Journal Title: Sci Rep Volume: 9 Pages: 1-13
  • DOI: 10.1038/s41598-019-49834-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histone H3K27 Demethylase Negatively Controls the Memory Formation of Antigen-Stimulated CD8+ T Cells (2019)
  • Author(s): Yamada Takeshi、Nabe Shogo、Toriyama Koji、Suzuki Junpei、Inoue Kazuki、Imai Yuuki、Shiraishi Atsushi、Takenaka Katsuto、Yasukawa Masaki、Yamashita Masakatsu
  • Journal Title: J Immunol. Volume: 202 Pages: 1088-1098
  • DOI: 10.4049/jimmunol.1801083
  • Peer Reviewed / Open Access
• [Journal Article] Safe childbirth for a type 1 antithrombin-deficient woman with novel mutation in the SERPINC1 gene undergoing antithrombin concentrate therapy. (2019)
  • Author(s): Ikeda Y, Yamanouchi J, Hato T, Yasukawa M, Takenaka K
  • Journal Title: Blood Coagulation and Fibrinolysis Volume: 30 Pages: 47-51
  • DOI: 10.1097/mbc.0000000000000785
  • Peer Reviewed
• [Journal Article] Comparison of outcomes of allogeneic transplantation for primary myelofibrosis among hematopoietic stem cell source groups. (2019)
  • Author(s): Murata M, Takenaka K, Uchida N, Ozawa Y, Ohashi K, Kim SW, Ikegame K, Kanda Y, Kobayashi H, Ishikawa J, Ago H, Hirokawa M, Fukuda T, Atsuta Y, Kondo T.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 25 Pages: 1536-1543
  • DOI: 10.1016/j.bbmt.2019.02.019
  • Peer Reviewed
• [Journal Article] Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer (2019)
  • Author(s): Nakano Michitaka、Kikushige Yoshikane、Miyawaki Kohta、Kunisaki Yuya、Mizuno Shinichi、Takenaka Katsuto、Tamura Shingo、Okumura Yuta、Ito Mamoru、Ariyama Hiroshi、Kusaba Hitoshi、Nakamura Masafumi、Maeda Takahiro、Baba Eishi、Akashi Koichi
  • Journal Title: Oncogene Volume: 38 Pages: 780-793
  • DOI: 10.1038/s41388-018-0480-0
  • Peer Reviewed / Open Access
• [Journal Article] Escape hematopoiesis by HLA-B5401-lacking hematopoietic stem progenitor cells in men with acquired aplastic anemia. (2019)
  • Author(s): Elbadry MI, Ogawa S.et al.,
  • Journal Title: Haematologica Volume: - Pages: 210856-210856
  • DOI: 10.3324/haematol.2018.210856
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] E-cadherin regulates proliferation of colorectal cancer stem cells through NANOG. (2018)
  • Author(s): Tamura S, Isobe T, Ariyama H, Nakano M, Kikushige Y, Takaishi S, Kusaba H, Takenaka K, Ueki T, Nakamura M, Akashi K, Baba E.
  • Journal Title: Oncol Rep Volume: 40 (2) Pages: 693-703
  • DOI: 10.3892/or.2018.6464
  • Peer Reviewed / Open Access
• [Journal Article] Recent advances in the diagnosis and management of primary myelofibrosis (2018)
  • Author(s): Takenaka Katsuto、Shimoda Kazuya、Akashi Koichi
  • Journal Title: Korean J Intern Med Volume: 33 Pages: 679-690
  • DOI: 10.3904/kjim.2018.033
  • Peer Reviewed / Open Access
• [Journal Article] Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack (2018)
  • Author(s): Espinoza J. Luis、Elbadry Mahmoud I.、Chonabayashi Kazuhisa、Yoshida Yoshinori、Katagiri Takamasa、Harada Kenichi、Nakagawa Noriharu、Zaimoku Yoshitaka、Imi Tatsuya、Hassanein Hassan A.、Khalifa A. Noreldin Amal、Takenaka Katsuto、Akashi Koichi、Hamana Hiroshi、Kishi Hiroyuki、Akatsuka Yoshiki、Nakao Shinji
  • Journal Title: Blood Adv. Volume: 2 Pages: 390-400
  • DOI: 10.1182/bloodadvances.2017013342
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reinforce the antitumor activity of CD8+ T cells via glutamine restriction (2018)
  • Author(s): Nabe Shogo、Yamada Takeshi、Suzuki Junpei、Toriyama Koji、Yasuoka Toshiaki、Kuwahara Makoto、Shiraishi Atsushi、Takenaka Katsuto、Yasukawa Masaki、Yamashita Masakatsu
  • Journal Title: Cancer Sci. Volume: 109 Pages: 3737-3750
  • DOI: 10.1111/cas.13827
  • Peer Reviewed / Open Access
• [Presentation] 再生不良性貧血に対する同種造血幹細胞移植後 サイトメガロウイルス再活性化の 移植後予後に及ぼす影響 (2021)
  • Author(s): 竹中克斗
  • Organizer: 第43回日本造血細胞移植学会
• [Presentation] PMF診療の最前線 (2020)
  • Author(s): 竹中克斗
  • Organizer: 第82回日本血液学会学術集会
  • Invited
• [Presentation] 血液疾患治療の最新の話題 (2020)
  • Author(s): 竹中克斗
  • Organizer: 第63回日本内科学会四国支部生涯教育講演会
  • Invited
• [Presentation] 移植後サイトメガロウイルス感染症に対する新たな戦略 (2019)
  • Author(s): 竹中克斗
  • Organizer: 第67回日本輸血・細胞治療学会学術集会
  • Invited
• [Presentation] 教育講演 MPNにおける同種造血幹細胞移植 (2019)
  • Author(s): 竹中克斗
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Clinical debate 7 MPN (2019)
  • Author(s): 竹中克斗
  • Organizer: 第81回日本血液学会学術集会