Elucidation of chemoradiation therapy resistance mechanism using pancreatic cancer cell derived three-dimensional organoids

• Project/Area Number: 16K19945
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kagoshima University
• Principal Investigator: KAWASAKI YOTA 鹿児島大学, 附属病院, 医員 (90770420)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 膵臓癌 / 化学療放射線感受性 / 抗酸化能力 / オルガノイドモデル / 食道癌 / 化学療法放射線感受性 / 化学放射線療法感受性 / *膵臓癌

Outline of Final Research Achievements

We generated 3D organoids from biopsies representing tumors from therapy-negative esophageal cancer patients. Tumor-derived 3D organoids were grown successfully from 15 out of 21 patients (71.4%). Successful formation of tumor-derived 3D organoids was associated significantly with poor response to presurgical neoadjuvant chemotherapy or chemoradiation therapy in informative patients (P=0.0357).
The single cell-based 3D organoid system may serve as a highly efficient platform to explore cancer therapeutics and therapy resistance mechanisms in conjunction with morphological and functional assays with implications for translation in personalized medicine.

Academic Significance and Societal Importance of the Research Achievements

膵臓癌は極めて予後不良な消化器癌の一つであり、正しい個別化治療の選択が予後に作用する。今回、食道扁平上皮癌検体を用いた3D培養、オルガノイド形成に世界初で成功し、形成できたオルガノイドを用いた化学療法に対する奏功度が、実臨床と相関していたことは、食道癌個別化治療の確立に大きく寄与しうると考えられる。確立できた3D培養、オルガノイド形成方法を膵臓癌検体で利用することで、今後、膵臓癌個別化治療の確立にも大きく寄与しうる可能性がある。

Research Products

• [Journal Article] Gene regulation by antitumor miR-130b-5p in pancreatic ductal adenocarcinoma: the clinical significance of oncogenic EPS8. (2019)
  • Author(s): Fukuhisa H, Seki N, Idichi T, Kurahara H, Yamada Y, Toda H, Kita Y, Kawasaki Y, Tanoue K, Mataki Y, Maemura K, Natsugoe S.
  • Journal Title: J Hum Genet. Volume: - Issue: 6 Pages: 521-534
  • DOI: 10.1038/s10038-019-0584-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] New scoring system for resectable hepatocellular carcinoma with a maximum tumor size of <5 cm based on preoperative tumor factors. (2019)
  • Author(s): Kawasaki Y, Yang SJ, Choi GH, Han DH, Lee JH, Iino S, Sakoda M, Ueno S, Natsugoe S, Choi JS.
  • Journal Title: HPB (Oxford) Volume: - Issue: 10 Pages: 1393-1399
  • DOI: 10.1016/j.hpb.2019.02.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gene Regulation by Antitumor miR-204-5p in Pancreatic Ductal Adenocarcinoma: The Clinical Significance of Direct RACGAP1 Regulation. (2019)
  • Author(s): Khalid M, Idichi T, Seki N, Wada M, Yamada Y, Fukuhisa H, Toda H, Kita Y, Kawasaki Y, Tanoue K, Kurahara H, Mataki Y, Maemura K, Natsugoe S.
  • Journal Title: Cancers (Basel) Volume: 11 Issue: 3 Pages: 327-327
  • DOI: 10.3390/cancers11030327
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Significance of 18F-Fluorodeoxyglucose (FDG) Uptake in Response to Chemoradiotherapy for Pancreatic Cancer (2019)
  • Author(s): Kurahara H, Maemura K, Mataki Y, Sakoda M, Iino S, Kawasaki Y, Arigami T, Mori S, Kijima Y, Ueno S, Shinchi H, Natsugoe S
  • Journal Title: Ann Surg Oncol Volume: 26 Issue: 2 Pages: 644-651
  • DOI: 10.1245/s10434-018-07098-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Usefulness of fluorescence vascular imaging for evaluating splenic perfusion (2018)
  • Author(s): Kawasaki Yota、Maemura Kosei、Kurahara Hiroshi、Mataki Yuko、Iino Satoshi、Sakoda Masahiko、Shinchi Hiroyuki、Natsugoe Shoji
  • Journal Title: ANZ journal of surgery Volume: not decided Issue: 10 Pages: 1017-1021
  • DOI: 10.1111/ans.14364
  • Peer Reviewed
• [Journal Article] Improved perioperative outcomes of laparoscopic distal pancreatosplenectomy: modified lasso technique (2017)
  • Author(s): Kawasaki Yota、Hwang Ho Kyoung、Kang Chang Moo、Natsugoe Shoji、Lee Woo Jung
  • Journal Title: ANZ journal of surgery Volume: not decided Issue: 9 Pages: 886-890
  • DOI: 10.1111/ans.14351
  • Peer Reviewed
• [Journal Article] Relationship between the surgical margin status, prognosis, and recurrence in extrahepatic bile duct cancer patients. (2017)
  • Author(s): Kurahara H, Maemura K, Mataki Y, Sakoda M, Iino S, Kawasaki Y, Mori S, Kijima Y, Ueno S, Shinchi H, Takao S, Natsugoe S.
  • Journal Title: Langenbeck's Archives of Surgery Volume: 402 Issue: 1 Pages: 87-93
  • DOI: 10.1007/s00423-016-1491-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gemcitabine and S-1 Induction Chemotherapy Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancers (2017)
  • Author(s): Maemura K, Mataki Y, Kurahara H, Kawasaki Y, Iino S, Sakoda M, Uchikado Y, Arigami T, Uenosono Y, Mori S, Ueno S, Shinchi H, Natsugoe S
  • Journal Title: anticancer research Volume: 37 Issue: 1 Pages: 233-237
  • DOI: 10.21873/anticanres.11312
  • Peer Reviewed
• [Journal Article] Preoperative biliary drainage-related inflammation is associated with shorter survival in biliary tract cancer patients (2016)
  • Author(s): Hiroshi Kurahara
  • Journal Title: International Journal of Clinical Oncology Volume: Ｅｐｕｂ ａｈｅａｄ ｏｆ ｐｒｉｎｔ Issue: 5 Pages: 934-939
  • DOI: 10.1007/s10147-016-0961-5
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Simple and easy method to isolate main pancreatic duct during pancreatoduodenectomy (2018)
  • Author(s): Yota Kawasaki, Kosei Maemura, Hiroshi Kurahara, Yuko Mataki, Kiyonori Tanoue, Motoyuki Hashiguchi, Satoshi Iino, Masahiko Sakoda, Shinichi Ueno, Hiroyuki Shinchi, Shoji Natsugoe
  • Organizer: 13th IHPBA World Congress
  • Int'l Joint Research
• [Presentation] Simple and easy method to isolate main pancreatic duct during pancreatoduodenectomy (2018)
  • Author(s): Yota Kawasaki, Kosei Maemura, Hiroshi Kurahara, Yuko Mataki, Kiyonori Tanoue, Motoyuki Hashiguchi, Satoshi Iino, Masahiko Sakoda, Shinichi Ueno, Hiroyuki Shinchi, Shoji Natsugoe
  • Organizer: 30th Meeting of Japanese Society of Hepato-Biliary-Pancreatic Surgery
• [Presentation] fluorescence vascular imaging systemを用いた脾臓血流評価の有用性 (2018)
  • Author(s): 川﨑洋太、南幸次、橋口真征、蔵原弘、飯野聡、又木雄弘 迫田雅彦、前村公成、上野真一、新地洋之、夏越祥次
  • Organizer: 第31回日本内視鏡外科学会
• [Presentation] 切除可能肝細胞癌における新規scoring system (2018)
  • Author(s): 川崎洋太、Gi Hong Choi、飯野聡 、迫田正彦 、上野真一、Jin Sub Choi、 夏越祥次
  • Organizer: 第118回日本外科学会
• [Presentation] 膵実質切離時の主膵管露出の工夫 (2018)
  • Author(s): 川崎洋太, 前村公成, 蔵原弘, 又木雄弘, 田上聖徳, 飯野聡, 迫田雅彦, 上野真一, 新地洋之, 夏越祥次
  • Organizer: 第80回日本臨床外科学会
• [Presentation] Benefit of using fluorescence vascular imaging for safe preservation of the spleen after distal pancreatectomy with the Warshaw technique， (2017)
  • Author(s): Yota Kawasaki
  • Organizer: JSHPBS
• [Presentation] Surgical approach for GIST arising from 4th portion duodenum (2017)
  • Author(s): Yota Kawasaki
  • Organizer: 21st Asian Congress of Surgery
• [Presentation] 食道扁平上皮癌におけるオルガノイド培養について (2017)
  • Author(s): 貴島 孝
  • Organizer: 日本消化器外科学会
• [Presentation] Development of novel pancreaticogastrostomy after pancreaticoduodenectomy aiming for the safest pancreas reconstruction (2016)
  • Author(s): Yota Kawasaki
  • Organizer: 日本消化器外科学会
  • Place of Presentation: あわぎんホール（徳島県徳島市）
  • Year and Date: 2016-07-14
• [Presentation] Improved Perioperative Outcomes of Laparoscopic Distal Pancreatosplenectomy by Modified Lasso Technique (2016)
  • Author(s): 川崎洋太
  • Organizer: 第8回膵臓内視鏡外科研究会
  • Place of Presentation: グランドプリンス新高輪（東京都港区）