Development of new immunotherapy for metastatic pancreatic cancer by applying organoids derived from circulating tumor cells in blood.

• Project/Area Number: 20K08956
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Yamaguchi University
• Principal Investigator: Tanabe Tsuyoshi 山口大学, 大学院医学系研究科, 教授 (80260678)
• Co-Investigator(Kenkyū-buntansha): 浅井 義之 山口大学, 大学院医学系研究科, 教授 (00415639) ; 山口 奈津 山口大学, 大学院医学系研究科, 助教 (40450671) ; 清木 誠 山口大学, 大学院医学系研究科, 教授 (50226619) ; 硲 彰一 山口大学, 医学部, 特別医学研究員 (50253159)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 膵がん / オルガノイド / 膵臓がん / 血中循環腫瘍細胞 / CTC

Outline of Research at the Start

膵がんは早期に転移するため予後不良だが、転移の治療法は確立していない。免疫療法は有力な候補だが、何を標的に免疫を誘導するかが問題となる。血中循環腫瘍細胞（CTC）は原発巣から血中に遊離し転移巣を形成する。本研究では、膵がんCTCからオルガノイドを作製し、これを標的として膵がん特異的キラーT細胞の誘導および膵がん特異的ネオ抗原の同定を行い、これを応用した新規免疫療法の開発を目指す。本研究により、従来の検出法では明らかな転移巣の存在が確認できない早期の段階から、ごく早期の転移巣を標的とした治療法を確立することができる。またこの手法は他のがん種に対しても応用可能である。

Outline of Final Research Achievements

In this study, we conducted the following studies based on the original conception of producing organoids from circulating tumor cells (CTCs) in the blood as a model of metastases and developing immunotherapy targeting them for the treatment of metastases.
(1) Since it was difficult to establish organoids from CTCs, we transplanted pancreatic cancer organoids established from a mouse pancreatic cancer model into mice and established a metastasis model. (2) To identify genes expressed in early metastases, we established a method using a spatial single-cell analysis method that can identify all immune cell types at the single-cell level. (3) Co-cultured CTC organoids with peripheral blood and successfully induced lymphocytes that specifically respond to pancreatic cancer.

Academic Significance and Societal Importance of the Research Achievements

膵がんは早期転移のため5年生存率は、全がんのなかで最低の12%であり、転移の治療法は確立していない。免疫療法は有力な治療法候補であるが、何を標的に免疫を誘導するかが問題となる。
本研究において樹立した解析系により、転移巣初期形成過程で発現する遺伝子をシングルセルRNAシーケンスで同定し、免疫治療の標的にできると考えられる。転移巣初期形成過程に特異的に発現する遺伝子は、膵臓がんの患者間で共通の可能性もある。そのような分子を標的にした抗体医薬や、CAR-T細胞は、膵がんの転移を抑制することが期待できる。

Research Products

• [Journal Article] Association of Plasma Branched-Chain and Aromatic Amino Acids with Reduction in Kidney Function Evaluated in Apparently Healthy Adults (2021)
  • Author(s): Mahbub MH、Yamaguchi Natsu、Nakagami Yuki、Hase Ryosuke、Takahashi Hidekazu、Ishimaru Yasutaka、Watanabe Rie、Saito Hiroyuki、Shimokawa Junki、Yamamoto Hiroshi、Kikuchi Shinya、Tanabe Tsuyoshi
  • Journal Title: Journal of Clinical Medicine Volume: 10 Issue: 22 Pages: 5234-5234
  • DOI: 10.3390/jcm10225234
  • Peer Reviewed
• [Journal Article] Analysis of Relationships between Immune Checkpoint and Methylase Gene Polymorphisms and Outcomes after Unrelated Bone Marrow Transplantation (2021)
  • Author(s): Takahashi Hidekazu、Okayama Naoko、Yamaguchi Natsu、Nomura Moe、Miyahara Yuta、Mahbub MH、Hase Ryosuke、Morishima Yasuo、Suehiro Yutaka、Yamasaki Takahiro、Tamada Koji、Takahashi Satoshi、Tojo Arinobu、Tanabe Tsuyoshi
  • Journal Title: Cancers Volume: 13 Issue: 11 Pages: 2752-2752
  • DOI: 10.3390/cancers13112752
  • Peer Reviewed / Open Access
• [Journal Article] A novel mutation in early‐onset sarcoidosis/Blau syndrome: an association with Propionibacterium acnes (2021)
  • Author(s): Okazaki Fumiko、Wakiguchi Hiroyuki、Korenaga Yuno、Nakamura Tamaki、Yasudo Hiroki、Uchi Shohei、Yanai Ryoji、Asano Nobuyuki、Hoshii Yoshinobu、Tanabe Tsuyoshi、Izawa Kazushi、Honda Yoshitaka、Nishikomori Ryuta、Uchida Keisuke、Eishi Yoshinobu、Ohga Shouichi、Hasegawa Shunji
  • Journal Title: Pediatric Rheumatology Volume: 19 Issue: 1 Pages: 18-18
  • DOI: 10.1186/s12969-021-00505-5
  • Peer Reviewed / Open Access
• [Journal Article] Gravity sensing in plant and animal cells. (2021)
  • Author(s): Takahashi K, Takahashi H, Furuichi T, Toyota M, Furutani-Seiki M, Kobayashi T, Watanabe-Takano H, Shinohara M, Numaga-Tomita T, Sakaue-Sawano A, Miyawaki A, Naruse K.
  • Journal Title: NPJ Microgravity Volume: 7 Issue: 1 Pages: 2-2
  • DOI: 10.1038/s41526-020-00130-8
  • Peer Reviewed / Open Access
• [Journal Article] Pancreatic Cancer Stem-Like Cells With High Calreticulin Expression Associated With Immune Surveillance (2021)
  • Author(s): Fujiwara Yasuhiro、Tsunedomi Ryouichi、Yoshimura Kiyoshi、Matsukuma Satoshi、Fujiwara Nobuyuki、Nishiyama Mitsuo、Kanekiyo Shinsuke、Matsui Hiroto、Shindo Yoshitaro、Tokumitsu Yukio、Yoshida Shin、Iida Michihisa、Suzuki Nobuaki、Takeda Shigeru、Ioka Tatsuya、Hazama Shoichi、Nagano Hiroaki
  • Journal Title: Pancreas Volume: 50 Issue: 3 Pages: 405-413
  • DOI: 10.1097/mpa.0000000000001772
  • Peer Reviewed / Open Access
• [Journal Article] Plasma Branched-Chain and Aromatic Amino Acids in Relation to Hypertension (2020)
  • Author(s): Mahbub M. H.、Yamaguchi Natsu、Hase Ryosuke、Takahashi Hidekazu、Ishimaru Yasutaka、Watanabe Rie、Saito Hiroyuki、Shimokawa Junki、Yamamoto Hiroshi、Kikuchi Shinya、Tanabe Tsuyoshi
  • Journal Title: Nutrients Volume: 12 Issue: 12 Pages: 3791-3791
  • DOI: 10.3390/nu12123791
  • Peer Reviewed / Open Access
• [Journal Article] Acute Effects of Whole-Body Vibration on Peripheral Blood Flow, Vibrotactile Perception and Balance in Older Adults (2020)
  • Author(s): Mahbub M. H.、Hase Ryosuke、Yamaguchi Natsu、Hiroshige Keiichi、Harada Noriaki、Bhuiyan A. N. M. Nurul Haque、Tanabe Tsuyoshi
  • Journal Title: International Journal of Environmental Research and Public Health Volume: 17 Issue: 3 Pages: 1069-1069
  • DOI: 10.3390/ijerph17031069
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ARHGAP29 expression may be a novel prognostic factor of cell proliferation and invasion in prostate cancer (2020)
  • Author(s): Shimizu Kosuke、Matsumoto Hiroaki、Hirata Hiroshi、Ueno Koji、Samoto Masahiro、Mori Junichi、Fujii Nakanori、Kawai Yoshihisa、Inoue Ryo、Yamamoto Yoshiaki、Yano Seiji、Shimabukuro Tomoyuki、Furutani-Seiki Makoto、Matsuyama Hideyasu
  • Journal Title: Oncology Reports Volume: 44 Issue: 6 Pages: 2735-2745
  • DOI: 10.3892/or.2020.7811
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic Protection of Vertebrate Lymphoid Progenitor Cells by Dnmt1 (2020)
  • Author(s): Iwanami Norimasa、Takeshita Kohei、Lawir Divine-Fondzenyuy、Suetake Isao、Tajima Shoji、Sikora Katarzyna、Trancoso In?s、?Meara Connor、Siamishi Iliana、Takahama Yousuke、Furutani-Seiki Makoto、Kondoh Hisato、Yonezawa Yasushige、Schorpp Michael、Boehm Thomas
  • Journal Title: iScience Volume: 23 Issue: 7 Pages: 101260-101260
  • DOI: 10.1016/j.isci.2020.101260
  • Peer Reviewed / Open Access / Int'l Joint Research