Diversity of molecular paths during pancreatic carcinogenesis

• Project/Area Number: 17K09472
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Asahikawa Medical College
• Principal Investigator: Mizukami Yusuke 旭川医科大学, 医学部, 教授 (30400089)
• Co-Investigator(Kenkyū-buntansha): 小野 裕介 医療法人徳洲会札幌東徳洲会病院医学研究所, 臨床生体情報解析部, 部門長 (40742648) ; 唐崎 秀則 医療法人徳洲会札幌東徳洲会病院医学研究所, 外科的消化器病疾患研究部, 副部門長 (50374806) ; 笹島 順平 旭川医科大学, 医学部, 客員講師 (80451467)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 膵癌 / 膵管内乳頭粘液性腫瘍 / GNAS / クローン進化 / 初代細胞 / IPMN / 細胞

Outline of Final Research Achievements

We aimed to clarify the role of two driver genes, KRAS and GNAS, on the pancreatic carcinogenesis using surgically resected pancreatic cancers associated with intraductal papillary mucinous neoplasm (IPMN). By molecular pathological analysis, new subtypes leading to the development of pancreatic cancer were found. We also clarified pancreatobiliary-type IPMN with wild-type GNAS is prone to residual pancreatic recurrence.
We also sought to clarify the downstream pathway of mutant GNAS and the effect on tumor phenotype using genetically engineered mouse models and genome-editing experiments using primary cells derived from human IPMN-related pancreatic cancer with mutant GNAS. The driver gene plays a role in tumor progression and maintenance by regulating mucin traits and tumor metabolic paths.
These findings are useful for stratifying the progression path of pancreatic carcinogenesis in IPMN patients and predicting the risk for developing malignant progression.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、膵癌の悪性化機構に関わる新知見をもたらす。膵癌の多様性を制御する分子機構への理解が深め膵癌進展ルートの層別化することで、新規バイオマーカーの発見による高リスク群のサーベイランス、早期診断を支える技術開発へと繋がる。また、特定の遺伝子異常に関わる腫瘍細胞の脆弱性を見出したことで、標準治療の在り方に変革をもたらすことが期待される。

Research Products

• [Int'l Joint Research] Mass Gen Hospital Cancer Center(米国)
• [Journal Article] Intraductal papillary neoplasms of the bile duct consist of two distinct types specifically associated with clinicopathological features and molecular phenotypes (2020)
  • Author(s): Aoki Yasutaka、Mizuma Masamichi、Hata Tatsuo、Aoki Takeshi、Omori Yuko、Ono Yusuke、Mizukami Yusuke、Unno Michiaki、Furukawa Toru
  • Journal Title: The Journal of Pathology Volume: 251 Issue: 1 Pages: 38-48
  • DOI: 10.1002/path.5398
  • Peer Reviewed / Open Access
• [Journal Article] Comparative genome-wide analysis of gastric adenocarcinomas with hyperplastic polyp components (2019)
  • Author(s): Yoshiyasu Takayama, Yusuke Ono, Yusuke Mizukami, Hideaki Itoh, Nozomi Nakajima, Hideo Arai, Shinya Tanaka, Sumihito Nobusawa, Hideaki Yokoo, Yasuhiro Onozato
  • Journal Title: Virchows Arch Volume: 475 Issue: 3 Pages: 383-389
  • DOI: 10.1007/s00428-019-02592-y
  • Peer Reviewed
• [Journal Article] Clinical course of conservative management for isolated superior mesenteric arterial dissection (2019)
  • Author(s): Sosogi Sho、Sato Ryu、Wada Reona、Saito Hiroya、Takauji Shuhei、Sakamoto Jun、Kimura Keisuke、 Karasaki Hidenori、Mizukami Yusuke、Ohta Tomoyuki
  • Journal Title: European Journal of Radiology Open Volume: 6 Pages: 192-197
  • DOI: 10.1016/j.ejro.2019.05.004
  • Peer Reviewed / Open Access
• [Journal Article] Metachronous intraductal papillary mucinous neoplasms disseminate via the pancreatic duct following resection (2019)
  • Author(s): Nagai Kazumasa、Mizukami Yusuke、Omori Yuko、Kin Toshifumi、Yane Kei、Takahashi Kuniyuki、Ono Yusuke、Sugitani Ayumu、Karasaki Hidenori、Shinohara Toshiya、Furukawa Toru、Hayashi Tsuyoshi、Okumura Toshikatsu、Maguchi Hiroyuki、Katanuma Akio
  • Journal Title: Modern Pathology Volume: 33 Issue: 5 Pages: 971-980
  • DOI: 10.1038/s41379-019-0405-7
  • Peer Reviewed / Open Access
• [Journal Article] Genetic analysis of postoperative recurrence of pancreatic cancer potentially owing to needle tract seeding during EUS-FNB. (2019)
  • Author(s): Kawabata H, Miyazawa Y, Sato H, Okada T, Hayashi A, Iwama T, Fujibayashi S, Goto T, Sasajima J, Takauji S, Fujiya M, Torimoto Y, Tanino M, Omori Y, Ono Y, Karasaki H, Mizukami Y, Okumura T.
  • Journal Title: Endosc Int Open. Volume: 7(12) Issue: 12 Pages: E1768-E1772
  • DOI: 10.1055/a-1034-7700
  • Peer Reviewed / Open Access
• [Journal Article] Lymph Node Metastasis From Gastroesophageal Cancer Successfully Treated by Nivolumab: A Case Report of a Young Patient. (2019)
  • Author(s): Kashima S, Tanabe H, Tanino M, Kobayashi Y, Murakami Y, Iwama T, Sasaki T, Kunogi T, Takahashi K, Ando K, Ueno N, Moriichi K, Fukudo M, Tasaki Y, Hosokawa M, Mizukami Y, Fujiya M, Okumura T.
  • Journal Title: Front Oncol. Volume: 9 Pages: 1375-1375
  • DOI: 10.3389/fonc.2019.01375
  • Peer Reviewed / Open Access
• [Journal Article] ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics and immune evasion of pancreatic cancer (2019)
  • Author(s): Hashimoto, S*., Furukawa, S*., Hashimoto, A*., Tsutaho, A., Fukao, A., Sakamura, Y., Parajuli, G., Onodera, Y., Otsuka, Y., Handa, H., Oikawa, T., Hata, S., Nishikawa Y., Mizukami, Y., Kodama, Y., Murakami M., Fujiwara, T., Hirano, S., and Sabe, H. (*Equally contributed)
  • Journal Title: Proceedings of the National Academy of the Sciences of the United States of America Volume: 116 Issue: 35 Pages: 17450-17459
  • DOI: 10.1073/pnas.1901765116
  • Peer Reviewed / Open Access
• [Journal Article] 特集 肝胆膵領域とゲノム医療新時代-遺伝子パネルがやってきた！- IPMNのゲノム解析. (2019)
  • Author(s): 林 明宏、水上裕輔、佐藤裕基、河端秀賢、岡田哲弘、後藤拓磨、河本 徹、小野裕介、唐崎秀則、奥村利勝.
  • Journal Title: 肝・胆・膵 Volume: 79 Pages: 1125-1133
• [Journal Article] Pathways of Progression From Intraductal Papillary Mucinous Neoplasm to Pancreatic Ductal Adenocarcinoma Based on Molecular Features (2019)
  • Author(s): Omori Y, Ono Y, Tanino M, Karasaki H, Yamaguchi H, Furukawa T, Enomoto K, Ueda J, Sumi A, Katayama J, Muraki M, Taniue K, Takahashi K, Ambo Y, Shinohara T, Nishihara H, Sasajima J, Maguchi H, Mizukami Y*, Okumura T, Tanaka S.
  • Journal Title: Gastroenterology Volume: 156 Issue: 3 Pages: 647-661
  • DOI: 10.1053/j.gastro.2018.10.029
  • Peer Reviewed / Open Access
• [Journal Article] Autofluorescence Imaging Reflects the Nuclear Enlargement of Tumor Cells as well as the Cell Proliferation Ability and Aberrant Status of the p53, Ki-67, and p16 Genes in Colon Neoplasms (2019)
  • Author(s): Moriichi K, Fujiya M, Kobayashi Y, Murakami Y, Iwama T, Kunogi T, Sasaki T, Ijiri M, Takahashi K, Tanaka K, Sakatani A, Ando K, Nomura Y, Ueno N, Kashima S, Ikuta K, Tanabe H, Mizukami Y, Saitoh Y, Okumura T.
  • Journal Title: Molecules Volume: 24 Issue: 6 Pages: 1106-1106
  • DOI: 10.3390/molecules24061106
  • Peer Reviewed / Open Access
• [Journal Article] Highly sensitive detection of ALK resistance mutations in plasma using droplet digital PCR (2018)
  • Author(s): Yoshida Ryohei、Sasaki Takaaki、Umekage Yasuhiro、Tanno Sachie、Ono Yusuke、Ogata Munehiko、Chiba Shinichi、Mizukami Yusuke、Ohsaki Yoshinobu
  • Journal Title: BMC Cancer Volume: 18 Issue: 1 Pages: 1136-1136
  • DOI: 10.1186/s12885-018-5031-0
  • Peer Reviewed / Open Access
• [Journal Article] A Case of Alpha-Fetoprotein-Producing Adenocarcinoma of the Esophagogastric Junction in which Long-Term Survival Was Achieved by Means of Individualized Multidisciplinary Therapy (2018)
  • Author(s): Tanaka Kazuyuki、Fujiya Mikihiro、Ijiri Masami、Takahashi Keitaro、Ando Katsuyoshi、Nomura Yoshiki、Ueno Nobuhiro、Kashima Shin、Goto Takuma、Sasajima Junpei、Ito Takahiro、Moriichi Kentaro、Mizukami Yusuke、Tanabe Hiroki、Okumura Toshikatsu
  • Journal Title: Journal of Gastrointestinal Cancer Volume: - Issue: 3 Pages: 617-620
  • DOI: 10.1007/s12029-018-0078-3
  • NAID: 120006496820
  • Peer Reviewed
• [Journal Article] Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism (2018)
  • Author(s): Patra Krushna C.、Kato Yasutaka、Mizukami Yusuke、Widholz Sebastian、Boukhali Myriam、Revenco Iulia、Grossman Elizabeth A.、Ji Fei、Sadreyev Ruslan I.、Liss Andrew S.、Screaton Robert A.、Sakamoto Kei、Ryan David P.、Mino-Kenudson Mari、Castillo Carlos Fernandez-del、Nomura Daniel K.、Haas Wilhelm、Bardeesy Nabeel
  • Journal Title: Nature Cell Biology Volume: 20 Issue: 7 Pages: 811-822
  • DOI: 10.1038/s41556-018-0122-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Utility of “liquid biopsy” using pancreatic juice for early detection of pancreatic cancer (2018)
  • Author(s): Okada Tetsuhiro、Iwano Hirotoshi、Ono Yusuke、Karasaki Hidenori、Sato Takayuki、Yamada Masataka、Omori Yuko、Sato Hiroki、Hayashi Akihiro、Kawabata Hidemasa、Goto Takuma、Sasajima Junpei、Takauji Shuhei、Nagashima Kazuo、Mizukami Yusuke、Okumura Toshikatsu
  • Journal Title: Endoscopy International Open Volume: 06 Issue: 12 Pages: E1454-E1461
  • DOI: 10.1055/a-0721-1747
  • Peer Reviewed / Open Access
• [Journal Article] Takayasu’s arteritis associated with eosinophilic gastroenteritis, possibly via the overactivation of Th17 (2018)
  • Author(s): Fujiya Mikihiro、Kashima Shin、Sugiyama Yuya、Iwama Takuya、Ijiri Masami、Tanaka Kazuyuki、Takahashi Keitaro、Ando Katuyoshi、Nomura Yoshiki、Ueno Nobuhiro、Goto Takuma、Moriichi Kentaro、Mizukami Yusuke、Okumura Toshikatsu、Sasajima Junpei、Fujishiro Daisuke、Okamoto Kensaku、Makino Yuichi
  • Journal Title: Gut Pathogens Volume: 10 Issue: 1 Pages: 22-22
  • DOI: 10.1186/s13099-018-0251-z
  • Peer Reviewed
• [Journal Article] The Incidence and Risk Factors of Venous Thromboembolism in Patients with Inflammatory Bowel Disease: A Prospective Multicenter Cohort Study (2018)
  • Author(s): Ando Katsuyoshi、Fujiya Mikihiro、Nomura Yoshiki、Inaba Yuhei、Sugiyama Yuya、Kobayashi Yu、Iwama Takuya、Ijiri Masami、Takahashi Keitaro、Ueno Nobuhiro、Kashima Shin、Moriichi Kentaro、Tanabe Hiroki、Mizukami Yusuke、Akasaka Kazumi、Fujii Satoshi、Yamada Satoshi、Nakase Hiroshi、Okumura Toshikatsu
  • Journal Title: Digestion Volume: NA Issue: 4 Pages: 1-9
  • DOI: 10.1159/000495289
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The incidence and risk factors of venous thromboembolism in Japanese inpatients with inflammatory bowel disease: a retrospective cohort study (2018)
  • Author(s): Ando Katsuyoshi、Fujiya Mikihiro、Nomura Yoshiki、Inaba Yuhei、Sugiyama Yuuya、Iwama Takuya、Ijiri Masami、Takahashi Keitaro、Tanaka Kazuyuki、Sakatani Aki、Ueno Nobuhiro、Kashima Shin、Moriichi Kentaro、Mizukami Yusuke、Okumura Toshikatsu
  • Journal Title: Intestinal Research Volume: 16 Issue: 3 Pages: 416-416
  • DOI: 10.5217/ir.2018.16.3.416
  • Peer Reviewed
• [Journal Article] An elevated expression of serum exosomal microRNA-191, -21, -451a of pancreatic neoplasm is considered to be efficient diagnostic marker (2018)
  • Author(s): Goto Takuma、Fujiya Mikihiro、Konishi Hiroaki、Sasajima Junpei、Fujibayashi Shugo、Hayashi Akihiro、Utsumi Tatsuya、Sato Hiroki、Iwama Takuya、Ijiri Masami、Sakatani Aki、Tanaka Kazuyuki、Nomura Yoshiki、Ueno Nobuhiro、Kashima Shin、Moriichi Kentaro、Mizukami Yusuke、Kohgo Yutaka、Okumura Toshikatsu
  • Journal Title: BMC Cancer Volume: 18 Issue: 1 Pages: 1-11
  • DOI: 10.1186/s12885-018-4006-5
  • Peer Reviewed / Open Access
• [Journal Article] Diversity of precursor lesions for pancreatic cancer: The genetics and biology of intraductal papillary mucinous neoplasm. (2017)
  • Author(s): Patra KC, Bardeesy N, Mizukami Y
  • Journal Title: Clin Transl Gastroenterol Volume: 8 Issue: 4 Pages: e86-e86
  • DOI: 10.1038/ctg.2017.3
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] An improved digital polymerase chain reaction protocol to capture low-copy KRAS mutations in plasma cell-free DNA by resolving ‘subsampling’ issues (2017)
  • Author(s): Ono Yusuke、Sugitani Ayumu、Karasaki Hidenori、Ogata Munehiko、Nozaki Reo、Sasajima Junpei、Yokochi Tomoki、Asahara Shingo、Koizumi Kazuya、Ando Kiyohiro、Hironaka Katsunori、Daito Tsutomu、Mizukami Yusuke
  • Journal Title: Molecular Oncology Volume: 11 Issue: 10 Pages: 1448-1458
  • DOI: 10.1002/1878-0261.12110
  • Peer Reviewed / Open Access
• [Presentation] リキッドバイオプシーによる膵癌診断 Liquid biopsy in pancreatic tumors; Challenges for early detection and surveillance. (2019)
  • Author(s): 水上裕輔、小野裕介、奥村利勝
  • Organizer: 第78回日本癌学会学術総会 Symposium22; Liquid biopsy
  • Invited
• [Presentation] デジタルPCRを用いた血漿遊離核酸からの膵腫瘍の検出－早期診断への活用に向けて－ Screening of mutations in circulating cell-free DNA for early-stage diagnosis and surveillance of pancreatic tumors. (2019)
  • Author(s): 小野裕介、唐崎秀則、水上裕輔.
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] デジタルPCRによるBRAF遺伝子変異検査は甲状腺乳頭癌のFNA正診率を向上させる BRAF mutation testing by dPCR improves the diagnosis accuracy of FNA for the papillary thyroid carcinoma (2019)
  • Author(s): 北崎アリサ、駒林優樹、小野裕介、木村太一、田中伸哉、長嶋和郎、水上裕輔.
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] IPMN関連膵癌の分子基盤と進展経路. (2019)
  • Author(s): 水上裕輔、大森優子、唐崎秀則.
  • Organizer: 第50回日本膵臓学会大会 パネルディスカッション
• [Presentation] 血漿遊離核酸を用いた膵腫瘍診断 (2019)
  • Author(s): 岡田哲弘、水上裕輔、河本 徹、林 明宏、佐藤裕基、河端秀賢、後藤拓磨、笹島順平、小泉一也、高橋邦幸、岩野博俊、浅原新吾、桑谷将城、唐崎秀則、奥村利勝.
  • Organizer: 第50回日本膵臓学会大会
• [Presentation] Capturing Pancreatic Tumor-derived Mutations from Fine Needle Aspiration Using Digital PCR. (2019)
  • Author(s): Ono Y, Hayashi A, Wada R, Suzuki M, Maeda C, Okada T, Sato H, Kawabata H, Goto T, Karasaki H, Mizukami Y, Okumura T.
  • Organizer: The 50th Anniversary Joint Meeting of APA & JPS
  • Int'l Joint Research
• [Presentation] The Temporal Order of KRAS and GNAS Mutations in Intraductal Papillary Mucinous Neoplasms of the Pancreas and Evolution to Invasive Carcinoma. (2019)
  • Author(s): Mizukami Y, Karasaki H, Ono Y, Omori Y, Hayashi A, Tachibana S, Sugiyama Y, Sato H, Kawabata H, Goto T, Fujiya M, Takahashi K, Katanuma A, Maguchi H, Furukawa T, Okumura T.
  • Organizer: The 50th Anniversary Joint Meeting of APA & JPS
  • Int'l Joint Research
• [Presentation] PATHWAYS OF PROGRESSION FROM INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM AND THE GENETIC DIVERSITY OF ASSOCIATED ORGAN FIELD. (2019)
  • Author(s): Mizukami Y, Omori Y, Ono Y, Karasaki H, Tanino M, Yamaguchi H, Furukawa T, Maguchi H, Tanaka S, Okumura T.
  • Organizer: DDW2019米国消化器病週間
  • Int'l Joint Research
• [Presentation] ABNORMAL ACTIVATION OF HNRNPA0 INHIBITS CANCER CELL APOPTOSIS AND PROMOTES EXCESSIVE MITOSIS IN CANCER CELLS. (2019)
  • Author(s): Konishi H, Fujiya M, Kita A, Tanaka H, Kashima S, Sakatani A, Dokoshi T, Ando K, Ueno N, Moriichi K, Iwama T, Takahashi K, Murakami Y, Ikuta K, Mizukami Y, Goto T, Okumura T.
  • Organizer: DDW2019米国消化器病週間
  • Int'l Joint Research
• [Presentation] Diversity of precursor lesions for pancreatic cancer: Genetics and biology of intraductal papillary mucinous neoplasm. (2018)
  • Author(s): Mizukami Y, Ono Y, Karasaki H, Omori Y, Ueda J, Okumura T
  • Organizer: 第77回日本癌学会学術総会 腫瘍別シンポジウム 2：胆肝膵悪性腫瘍における現況と展望
  • Invited
• [Presentation] A revised model of clonal evolution of intraductal papillary mucinous neoplasm-related pancreatic carcinogenesis (2018)
  • Author(s): Mizukami Y, Omori Y, Ono Y, Karasaki H, Tanino M, Yamaguchi H, Furukawa T, Takahashi K Ambo Y, Shinohara T, Sasajima J, Tanaka S, Maguchi H
  • Organizer: Digestive Disease Week 2018. Research Forum: Pancreatic Cystic Neoplasms, IPMN and Neuroendocrine Tumors
  • Int'l Joint Research
• [Presentation] Plasma DNA genotyping using digital PCR for surveillance of pancreatic cancer in high-risk individuals (2017)
  • Author(s): Mizukami Y、Ono Y、Karasaki H、Koizumi K、Okada T、Sasajima J、Yamada M、Asahara S、Kawakubo K、Maguchi H
  • Organizer: 25th UEG Week
  • Int'l Joint Research
• [Presentation] An improved digital polymerase chain reaction protocol to capture low-copy KRAS mutations in plasma cell-free DNA by resolving ”subsampling”issues (2017)
  • Author(s): Ono Y、Sugitani A、Karasaki H、Ogata M、Nozaki R、Sasajima J、Mizukami Y
  • Organizer: 25th UEG Week
  • Int'l Joint Research
• [Presentation] Concomitant pancreatic cancers arising adjacent to index IPMN share identical KRAS mutations and are associated with a favorable prognosis (2017)
  • Author(s): Omori Y、Ono Y、Tanino M、Karasaki H、Shinohara T、Tanaka S、Maguchi H、Mizukami Y
  • Organizer: 25th UEG Week
  • Int'l Joint Research
• [Presentation] 血漿遊離核酸を用いた膵腫瘍悪性度診断 (2017)
  • Author(s): 岡田哲弘、水上裕輔、笹島順平、小野裕介、唐崎秀則、他
  • Organizer: 第25回日本消化器病関連学会週間
• [Presentation] Digital PCR-based liquid biopsy for early detection of pancreatic cancer (2017)
  • Author(s): Mizukami Y、Ono Y、Karasaki H、Okada T、Sasajima J
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Improved digital PCR protocol to capture low-copy KRAS mutations in plasma cell-free DNA by pre-amplification 血漿由来遊離核酸より微量変異を検出する感度の向上を目的としたデジタルPCR法の応用 (2017)
  • Author(s): Ono Y、Karasaki H、Sasajima J、Mizukami Y
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Liquid biopsyによる早期発見、再発転移の評価システムの開発（Liquid biopsy for Cancer Screening & Detection） (2017)
  • Author(s): 水上裕輔
  • Organizer: 第15回日本臨床腫瘍学会学術総会
• [Presentation] 膵臓がん CTOS 培養法と臨床応用 (2017)
  • Author(s): 水上裕輔
  • Organizer: 第30回日本動物実験代替法学会
• [Remarks] 膵嚢胞性腫瘍術後再発のパターンを解明－膵がんの早期発見や再発予測に期待－
  • URL: https://www.higashi-tokushukai.or.jp/inst_biomed_res/info/details/post_33.html
• [Remarks] 治療経過が良い胆管がん（胆管内乳頭状腫瘍）の判別が可能に
  • URL: http://www.tohoku.ac.jp/japanese/2020/02/press20200227-01-tan.html