Development of a new molecular diagnostic method and molecular targeted therapies for pancreatic ductal adenocarcinomas using RHO pathway-regulating proteins

• Project/Area Number: 16K08684
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Hokkaido University
• Principal Investigator: Mitsuhashi Tomoko 北海道大学, 大学病院, 准教授 (60348208)
• Co-Investigator(Kenkyū-buntansha): 畑中 豊 北海道大学, 大学病院, 特任准教授 (30589924)
• Project Period (FY): 2016-04-01 – 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 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); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 浸潤性膵管癌 / RHO経路 / 治療効果予測 / 病理学 / 癌 / ゲノム

Outline of Final Research Achievements

In this study, basic experiments were performed for the development of a new molecular diagnostic method and molecular targeted therapies for pancreatic ductal adenocarcinomas (PDACs), by focusing on multiple RHO pathway-regulating (RPR) proteins identified in our preceding studies. Gene expression profiling (GEP) data of RPR proteins was analyzed using public microarray data of PDAC cell lines. Twenty-one PDAC cell lines were divided into 3 clusters (Cluster 1 to 3), of which, Clusters 3 and 2 corresponded to QM and CL subtype of PDAC, respectively, as previously reported by Collison et al. Furthermore, the results of GEP data of EUS-FNA biopsies were also similar to those from PDAC cell lines. Thus, the molecular subtypes, reflecting the molecular pathophysiology and effectiveness of chemotherapy, could be associated with PRP gene expression profiles. Furthermore, results of this study can aid the development of molecular diagnostic methods and molecular targeted therapies for PDAC.

Academic Significance and Societal Importance of the Research Achievements

本研究により，Collisonらの提唱する膵癌の分子サブタイプと複数のRHO経路制御（RPR）分子（ARHGAP/ARHGEF）遺伝子発現プロファイルが関係することが示唆され，予後不良な膵癌の個別化治療に応用しうる膵癌分子診断法の開発に繋がる可能性を有する．RHO経路に関わる分子の遺伝子発現シグネチャーに着目した研究はこれまでにないことから，学術的意義が大きいといえる．またこの経路を阻害する薬剤はすでに開発されていることから，標的治療法の開発に繋がる可能性も有する．

Research Products

• [Journal Article] Hepatobiliary and Pancreatic: Hemosuccus pancreaticus due to an intraductal papillary mucinous neoplasm: A rare cause of obscure gastrointestinal bleeding. (2020)
  • Author(s): Sugiura R, Kinoshita K, Naruse H, Yamamoto Y, Hatanaka K, Ito J, Miyamoto S, Higashino M, Hayasaka S, Tsuchida N, Nakanishi K, Ueki S, Umehara M, Shimoyama N, Mitsuhashi T, Sakamoto N.
  • Journal Title: J Gastroenterol Hepatol. Volume: 35 Issue: 3 Pages: 363-363
  • DOI: 10.1111/jgh.14881
• [Journal Article] Signaling adaptor protein Crk is involved in malignant feature of pancreatic cancer associated with phosphorylation of c-Met. (2020)
  • Author(s): Uemura S, Wang L, Tsuda M, Suzuka J, Tanikawa S, Sugino H, Nakamura T, Mitsuhashi T, Hirano S, Tanaka S.
  • Journal Title: Biochem Biophys Res Commun Volume: 524 Issue: 2 Pages: 378-384
  • DOI: 10.1016/j.bbrc.2020.01.105
  • Peer Reviewed / Open Access
• [Journal Article] Validation Study of Tumor Invasive Thickness for Postoperative Prognosis in 110 Patients Who Underwent Pancreatoduodenectomy for Distal Cholangiocarcinoma at a Single Institution (2019)
  • Author(s): Yang Zhao, Yoshitsugu Nakanishi , Mariko Ogino, Mitsunobu Oba, Keisuke Okamura, Takahiro Tsuchikawa, Toru Nakamura, Takehiro Noji, Toshimichi Asano, Kimitaka Tanaka, Tomoko Mitsuhashi, Chaoliu Dai, and Satoshi Hirano
  • Journal Title: American Journal of Surgical Pathology Volume: 43(5) Issue: 5 Pages: 717-723
  • DOI: 10.1097/pas.0000000000001244
  • Peer Reviewed
• [Journal Article] Impact of Tumour Budding Grade in 310 Patients Who Underwent Surgical Resection for Extrahepatic Cholangiocarcinoma. (2019)
  • Author(s): Ogino M, Nakanishi Y, Mitsuhashi T, Hatanaka Y, Amano T, Marukawa K, Nitta T, Ueno T, Ono M, Kuwabara S, Yamada T, Hirano S.
  • Journal Title: Histopathology. Volume: 「印刷中」 Issue: 6 Pages: 861-872
  • DOI: 10.1111/his.13827
  • Peer Reviewed / Open Access
• [Journal Article] A Consensus Study of the Grading and Typing of Intraductal Papillary Mucinous Neoplasms of the Pancreas. (2019)
  • Author(s): Furukawa T, Fukushima N, Itoi T, Ohike N, Mitsuhashi T, Nakagohri T, Notohara K, Shimizu M, Tajiri T8, Tanaka M9, Yamaguchi H, Yanagisawa A, Sugiyama M, Okazaki K.
  • Journal Title: Pancreas. Volume: 3(48) Issue: 4 Pages: 480-487
  • DOI: 10.1097/mpa.0000000000001270
  • Peer Reviewed
• [Journal Article] Metastatic mixed adenoneuroendocrine carcinoma of the liver successfully resected by hepatic trisectionectomy following chemotherapy: A case report. (2019)
  • Author(s): Sato O, Tsuchikawa T, Yamada T, Sato D, Nakanishi Y, Asano T, Noji T, Yo K, Ebihara Y, Murakami S, Nakamura T, Okamura K, Shichinohe T, Mitsuhashi T, Hirano S.
  • Journal Title: Clin Case Rep. Volume: 7(3) Issue: 3 Pages: 491-496
  • DOI: 10.1002/ccr3.1968
  • Peer Reviewed
• [Journal Article] Prospective, multicenter, observational study of tissue acquisition through EUS-guided fine-needle biopsy using a 25G Franseen needle. (2019)
  • Author(s): Sugiura R, Kuwatani M, Yane K, Taya Y, Ihara H, Onodera M, Eto K, Sano I, Kudo T, Mitsuhashi T, Katanuma A, Sakamoto N; Hokkaido Interventional EUS/ERCP study (HONEST) group.
  • Journal Title: Endosc Ultrasound. Volume: 「印刷中」 Issue: 5 Pages: 321-321
  • DOI: 10.4103/eus.eus_66_18
  • Peer Reviewed
• [Journal Article] Cytoplasmic CD133 expression correlates with histologic differentiation and is a significant prognostic factor in extrahepatic bile duct cancer and gallbladder cancer. (2018)
  • Author(s): Mizukami T, Kamachi H, Mitsuhashi T, Einama T, Hatanaka Y, Kamiyama T, Taketomi A.
  • Journal Title: Oncol Lett. Volume: 16(5) Pages: 6423-6430
  • DOI: 10.3892/ol.2018.9499
  • Peer Reviewed
• [Journal Article] Clinicopathological features and prognosis of advanced biliary carcinoma centered in the cystic duct. (2018)
  • Author(s): Nakanishi Y, Tsuchikawa T, Okamura K, Nakamura T, Noji T, Asano T, Tanaka K, Shichinohe T, Mitsuhashi T, Hirano S.
  • Journal Title: HPB (Oxford) Volume: 20 Issue: 1 Pages: 28-33
  • DOI: 10.1016/j.hpb.2017.08.014
• [Journal Article] Genomic Characterization of Biliary Tract Cancers Identifies Driver Genes and Predisposing Mutations (2018)
  • Author(s): Wardell CP, Fujita M, Yamada T, Simbolo M, Fassan M, Karlic R, Polak P, Kim J, Hatanaka Y, Maejima K, Lawlor RT, Nakanishi Y, Mitsuhashi T et al
  • Journal Title: J Hepatol Volume: - Issue: 5 Pages: 959-969
  • DOI: 10.1016/j.jhep.2018.01.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of serum CA19-9 level on prognosis and prediction of lymph node metastasis in patients with intrahepatic cholangiocarcinoma. (2018)
  • Author(s): Yamada T, Nakanishi Y, Okamura K, Tsuchikawa T, Nakamura T, Noji T, Asano T, Tanaka K, Kurashima Y, Ebihara Y, Murakami S, Shichinohe T, Mitsuhashi T, Hirano S.
  • Journal Title: J Gastroenterol Hepatol. Volume: - Issue: 9 Pages: 1626-1633
  • DOI: 10.1111/jgh.14124
• [Journal Article] Identification of novel serum autoantibodies against EID3 in non-functional pancreatic neuroendocrine tumors. (2017)
  • Author(s): Hontani K, Tsuchikawa T, Hiwasa T, Nakamura T, Ueno T, Kushibiki T, Takahashi M, Inoko K, Takano H, Takeuchi S, Dosaka-Akita H, Kuwatani M, Sakamoto N, Hatanaka Y, Mitsuhashi T, Shimada H, Shichinohe T, Hirano S.
  • Journal Title: Oncotarget Volume: 8 Issue: 63 Pages: 106206-106221
  • DOI: 10.18632/oncotarget.22175
  • NAID: 120006416017
  • Peer Reviewed / Open Access
• [Journal Article] ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma (2016)
  • Author(s): Terashita K, Chuma M, Hatanaka Y, Hatanaka K, Mitsuhashi T, Yokoo H, Ohmura T, Ishizu H, Muraoka S, Nagasaka A, Tsuji T, Yamamoto Y, Kurauchi N, Shimoyama N, Toyoda H, Kumada T, Kaneoka Y, Maeda A, Ogawa K, Natsuizaka M, Kamachi H, Kakisaka T, Kamiyama T, Taketomi A, Matsuno Y, Sakamoto N
  • Journal Title: J Clin Pathol Volume: in press Issue: 7 Pages: 593-599
  • DOI: 10.1136/jclinpath-2015-203115
  • Peer Reviewed
• [Journal Article] Stromal Palladin Expression Is an Independent Prognostic Factor in Pancreatic Ductal Adenocarcinoma (2016)
  • Author(s): Sato D, Tsuchikawa T, Mitsuhashi T, Hatanaka Y, Marukawa K, Morooka A, Nakamura T, Shichinohe T, Matsuno Y, Hirano S
  • Journal Title: PLoS One Volume: 11 Issue: 3 Pages: e0152523-e0152523
  • DOI: 10.1371/journal.pone.0152523
  • NAID: 120005757988
  • Peer Reviewed / Open Access
• [Journal Article] The impact of margin status determined by the one-millimeter rule on tumor recurrence and survival following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. (2016)
  • Author(s): Nitta T, Nakamura T, Mitsuhashi T, Asano T, Okamura K, Tsuchikawa T, Tamoto E, Murakami S, Noji T, Kurashima Y, Ebihara Y, Nakanishi Y, Shichinohe T, Hirano S.
  • Journal Title: Surg Today Volume: Epub ahead of print
  • NAID: 120006415997
  • Peer Reviewed
• [Presentation] 膵癌の治療選択に有用なIHC分子サブタイピング法の確立に関する検討（ワークショップ 膵胆道系腫瘍における分子病理学的知見の進歩 基礎から臨床応用まで） (2018)
  • Author(s): 三橋 智子，丸川 活司，畑中 豊，松野 吉宏
  • Organizer: 第107回日本病理学会総会
• [Presentation] 膵管癌分子サブタイピングのIHCサロゲート法の確立に関する検討 (2018)
  • Author(s): 丸川 活司，三橋 智子，畑中 豊，諸岡 亜早美，佐藤 大介，奥村 麻美，南家 綾江，畑中 佳奈子，平野 聡，松野 吉宏
  • Organizer: 第107回日本病理学会総会
• [Presentation] von Hippel-Lindau病患者に発生した多形性に富む膵神経内分泌腫瘍（pleomorphic panNET）の一例 (2018)
  • Author(s): 出口 貴祥，丸川 活司，清水 知浩，恩田 千景，後藤 久美，安孫子 光春，岡田 宏美，高桑 恵美，三橋 智子，松野 吉宏
  • Organizer: 第59回日本臨床細胞学会総会(春期大会)
• [Presentation] 神経内分泌腫瘍および充実性偽乳頭状腫瘍などの細胞診の実践 (2017)
  • Author(s): 三橋 智子
  • Organizer: 第56回日本臨床細胞学会秋期大会
• [Presentation] 膵管内乳頭粘液性腫瘍の膵液細胞診について (2016)
  • Author(s): 三橋 智子
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2016-05-12
  • Invited
• [Presentation] 膵管癌におけるNT5E発現における臨床病理学的検討 (2016)
  • Author(s): 諸岡 亜早美，畑中 豊，丸川 活司，上野 峰，佐藤 大介，平野 裕子，奥村 麻美，清水 知浩，畑中 佳奈子，三橋 智子，松野 吉宏
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2016-05-12
• [Presentation] 低分化肝外胆管癌における臨床病理学的因子の検討 (2016)
  • Author(s): 上野 峰，三橋 智子，畑中 豊，岡村 圭祐，平野 聡，松野 吉宏
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2016-05-12
• [Book] 診断アプローチ，FNA 診断 腫瘍性疾患、炎症性疾患（膵臓を診る医師のための 膵臓病理テキスト） (2020)
  • Author(s): 三橋智子
  • Publisher: 南江堂
• [Book] 臨床医に伝わる報告書の書き方（手技と細胞鑑別の完全攻略 実践的EUS-FNAアトラス ～細胞検査士と内視鏡医に贈る） (2019)
  • Author(s): 三橋智子
  • Publisher: 医歯薬出版
  • ISBN: 9784263226872