Elucidation of molecular mechanism for pancreato-biliary cancer progression through EMT plasticity

• Project/Area Number: 15H04925
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Chiba University
• Principal Investigator: Takano Shigetsugu 千葉大学, 大学院医学研究院, 助教 (20436380)
• Co-Investigator(Kenkyū-buntansha): 高屋敷 吏 千葉大学, 大学院医学研究院, 講師 (30456024) ; 吉富 秀幸 千葉大学, 大学院医学研究院, 准教授 (60375631) ; 宮崎 勝 国際医療福祉大学, 大学病院, 教授 (70166156) ; 酒井 望 千葉大学, 医学部附属病院, 助教 (70436385) ; 賀川 真吾 千葉大学, 医学部附属病院, 助教 (90507302)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥13,390,000 (Direct Cost: ¥10,300,000、Indirect Cost: ¥3,090,000)
• Keywords: 膵癌 / Prrx1 / Metadherin / 中和抗体 / Epithelial plasticity / EMT / MET / 転移 / 膵臓外科学 / 浸潤・転移 / 浸潤、転移

Outline of Final Research Achievements

Epithelial-mesenchymal transition (EMT) is believed to be important for primary tumor progression and dissemination, whereas mesenchymal-epithelial transition (MET) appears crucial for metastatic colonization. We described novel roles for two Prrx1 isoforms in the metastatic cascade using in vitro and in vivo models of PDAC. Prrx1b promotes invasion and EMT, whereas Prrx1a stimulates metastatic outgrowth in the liver and MET. We further demonstrate that the switch from Prrx1b to Prrx1a governs EMT plasticity both in mouse models of PDAC as well as in human PDAC. Lastly, we identify hepatocyte growth factor (HGF) as a novel transcriptional target of Prrx1b. Targeted therapy of HGF in combination with gemcitabine in a preclinical model of PDAC eliminates metastatic disease. We provide new insights into the isoform-specific roles of Prrx1a and Prrx1b in primary PDAC formation, dissemination and metastatic colonization, allowing for novel therapeutic strategies targeting EMT plasticity.

Research Products

• [Journal Article] ETV5 regulates ductal morphogenesis with Sox9 and is critical for regeneration from pancreatitis. (2018)
  • Author(s): Das KK, Heeg S, Pitarresi JR, Reichert M, Bakir B, Takano S, Kopp JL, Wahl-Feuerstein A, Hicks P, Sander M, Rustgi AK.
  • Journal Title: Dev Dyn Volume: 印刷中 Issue: 6 Pages: 854-866
  • DOI: 10.1002/dvdy.24626
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Expression of annexin II and stromal tenascin C promotes epithelial to mesenchymal transition and correlates with distant metastasis in pancreatic cancer (2018)
  • Author(s): NAOKO YONEURA, SHIGETSUGU TAKANO, HIDEYUKI YOSHITOMI, YASUYUKI NAKATA, REIRI SHIMAZAKI, SHINGO KAGAWA, KATSUNORI FURUKAWA, TSUKASA TAKAYASHIKI, SATOSHI KUBOKI, MASARU MIYAZAKI and MASAYUKI OHTSUKA
  • Journal Title: Int J Mol Med Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Metadherin promotes metastasis by supporting putative cancer stem cell properties and epithelial plasticity in pancreatic cancer (2017)
  • Author(s): Suzuki K, Takano S, Yoshitomi H, Nishino H, Kagawa S, Shimizu H, Furukawa K, Miyazaki M, Ohtsuka M
  • Journal Title: Oncotarget Volume: 8 Issue: 39 Pages: 66098-66111
  • DOI: 10.18632/oncotarget.19802
  • Peer Reviewed / Open Access
• [Journal Article] Sex Determining Region Y Box 9 Induces Chemoresistance in Pancreatic Cancer Cells by Induction of Putative Cancer Stem Cell Characteristics and Its High Expression Predicts Poor Prognosis (2017)
  • Author(s): Higashihara T, Yoshitomi H, Nakata Y, Kagawa S, Takano S, Shimizu H, Kato A, Furukawa K, Ohtsuka M, Miyazaki M
  • Journal Title: Pancreas Volume: 46 Issue: 10 Pages: 1296-1304
  • DOI: 10.1097/mpa.0000000000000945
  • Peer Reviewed
• [Journal Article] Grainyhead-like 2 (GRHL2) regulates epithelial plasticity in pancreatic cancer progression (2017)
  • Author(s): Nishino H, Takano S, Yoshitomi H, Suzuki K, Kagawa S, Shimazaki R, Shimizu H, Furukawa K, Miyazaki M, Ohtsuka M
  • Journal Title: Cancer Med Volume: 6 Issue: 11 Pages: 2686-2696
  • DOI: 10.1002/cam4.1212
  • Peer Reviewed / Open Access
• [Journal Article] Development of a sandwich ELISA for the thrombin light chain identified by serum proteome analysis. (2017)
  • Author(s): Sogawa K, Kobayashi K, Kikkawa S, Takano S, Yoshitomi H, Takizawa H, Ohtsuka M, Shimizu H, Furuhata K, Miyazaki M, Yokosuka O, Nomura F.
  • Journal Title: Pract Lab Med Volume: 8 Pages: 34-40
  • DOI: 10.1016/j.plabm.2017.04.004
  • Peer Reviewed
• [Journal Article] Immune-complex level of cofilin-1 in sera is associated with cancer progression and poor prognosis in pancreatic cancer. (2017)
  • Author(s): Satoh M, Takano S, Sogawa K, Noda K, Yoshitomi H, Ishibashi M, Mogushi K, Takizawa H, Otsuka M, Shimizu H, Miyazaki M, Nomura F.
  • Journal Title: Cancer Sci. Volume: 印刷中 Issue: 4 Pages: 795-803
  • DOI: 10.1111/cas.13181
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization (2016)
  • Author(s): Shigetsugu Takano, Maximilian Reichert, Basil Bakir, Koushik K. Das, Takahiro Nishida, Masaru Miyazaki, Steffen Heeg, Meredith A. Collins, Benoît Marchand, Philip D. Hicks, Anirban Maitra, and Anil K. Rustgi
  • Journal Title: GENES & DEVELOPMENT Volume: 30 Issue: 2 Pages: 233-247
  • DOI: 10.1101/gad.263327.115
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ETS-Transcription Factor ETV1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer. (2016)
  • Author(s): Heeg S, Das KK, Reichert M, Bakir B, Takano S, Caspers J, Aiello NM, Wu K, Neesse A, Maitra A, Iacobuzio-Donahue CA, Hicks P, Rustgi AK.
  • Journal Title: Gastroenterology. Volume: 151 Issue: 3 Pages: 540-553
  • DOI: 10.1053/j.gastro.2016.06.005
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Identification of a novel serum biomarker for pancreatic cancer, C4b-binding protein α-chain (C4BPA) by quantitative proteomic analysis using tandem mass tags. (2016)
  • Author(s): Sogawa K, Takano S, Iida F, Satoh M, Tsuchida S, Kawashima Y, Yoshitomi H, Sanda A, Kodera Y, Takizawa H, Mikata R, Ohtsuka M, Shimizu H, Miyazaki M, Yokosuka O, Nomura F.
  • Journal Title: Br J Cancer. Volume: 115 Issue: 8 Pages: 949-956
  • DOI: 10.1038/bjc.2016.295
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A clinical application for molecular therapy against pancreatic cancer by targeting Prrx1 (2016)
  • Author(s): 高野重紹、Basil Bakir、Koushik K Das、西 田孝宏、吉富秀幸、宮崎勝、Maximilian Reichert
  • Journal Title: Suizo Volume: 31 Issue: 1 Pages: 41-47
  • DOI: 10.2958/suizo.31.41
  • NAID: 130005137847
  • ISSN: 0913-0071, 1881-2805
  • Peer Reviewed
• [Presentation] 膵癌早期診断バイオマーカーとしての血清C4BPA値の意義 (2017)
  • Author(s): 高野重紹、曽川一幸、吉富秀幸、清水宏明、古川勝規、高屋敷 吏、久保木 知、鈴木大亮、酒井 望、賀川真吾、野島広之、野村文夫、宮崎 勝、大塚将之
  • Organizer: 日本膵臓学会
• [Presentation] Identification of a novel serum biomarker for pancreatic cancer, C4b-binding protein alpha-chain (C4BPA) by quantitative proteomic analysis using tandem mass tag (2017)
  • Author(s): 高野重紹、曽川一幸、吉富秀幸、清水宏明、古川勝規、高屋敷 吏、久保木 知、鈴木大亮、酒井 望、賀川真吾、野島広之、野村文夫、宮崎 勝、大塚将之
  • Organizer: 日本外科学会
• [Presentation] A novel serum biomarker for pancreatic cancer, C4BPA is identified by comprehensive quantitative proteomics analysis (2017)
  • Author(s): Shigetsugu Takano, Kazuyuki Sogawa, Hideyuki Yoshitomi, Masaru Miyazaki, Fumio Nomura, Masayuki Ohtsuka
  • Organizer: 日本癌学会
• [Presentation] Two Prrx1 isoforms facilitate metastasis with cancer stem cell functions in pancreatic cancer. (2016)
  • Author(s): Shigetsugu Takano, Maximilian Reichert, Hideyuki Yoshitomi, Basil Bakir, Shingo Kagawa, Kensuke Suzuki, Masayuki Ohtsuka, Masaru Miyazaki, Anil K Rustgi
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、横浜、神奈川
  • Year and Date: 2016-10-06
• [Presentation] Prrx1 isoform regulate pancreatic cancer stem cell function during pancreatic cancer progression. (2016)
  • Author(s): Shigetsugu Takano, Maximilian Reichert, Hideyuki Yoshitomi, Basil Bakir, Koushik K Das, Steffen Heeg, Shingo Kagawa, Hiroaki Shimizu, Masayuki Ohtsuka, Katsunori Furukawa, Masaru Miyazaki, Anil K Rustgi
  • Organizer: 3rd AACR Special Conference, Pancreatic Cancer: Advances in Science and Clinical Care
  • Place of Presentation: Florida, USA
  • Year and Date: 2016-05-12
  • Int'l Joint Research
• [Presentation] Prrx1 isoformとgemcitabine耐性及びCD133との関連 (2015)
  • Author(s): 高野重紹、吉富秀幸、清水宏明、大塚将之、加藤厚、古川勝規、高屋敷吏、久保木 知、鈴木大亮、酒井 望、賀川真吾、野島広之、宮崎 勝
  • Organizer: 第10回膵癌術前治療研究会
  • Place of Presentation: 大宮ソニックシティ（埼玉・大宮）
  • Year and Date: 2015-09-19
• [Presentation] 膵癌進展～浸潤転移を制御するPrrx1b-Hgf axisの意義 (2015)
  • Author(s): 高野重紹、Maximilian Reichert、吉富秀幸、清水宏明、大塚将之、加藤厚、 古川勝規、高屋敷吏、Anil K Rustgi、宮崎 勝
  • Organizer: 第70回日本消化器外科学会総会
  • Place of Presentation: アクトシティー浜松（静岡・浜松）
  • Year and Date: 2015-07-15
• [Presentation] Prrx1を標的とした膵癌の個別化分子治療への応用 (2015)
  • Author(s): 高野重紹、吉富秀幸、清水宏明、大塚将之、加藤厚、古川勝規、高屋敷 吏、久保木知、岡村大樹、鈴木大亮、酒井望、賀川真吾、Anil K Rustgi、宮崎勝
  • Organizer: 第46回日本膵臓学会大会
  • Place of Presentation: 名古屋国際会議場（名古屋・名古屋）
  • Year and Date: 2015-06-19