Pancreatic-Intestinal Crosstalk: a novel approach to elucidate the tumorigenic process of PDAC

• Project/Area Number: 15K14716
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Applied biochemistry
• Research Institution: Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital
• Principal Investigator: ONO Yusuke 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)
• Co-Investigator(Kenkyū-buntansha): 水上 裕輔 医療法人徳洲会札幌東徳洲会病院医学研究所, がん研究部, 部門長 (30400089) ; 前本 篤男 医療法人徳洲会札幌東徳洲会病院医学研究所, IBD研究部, 部門長 (40400113) ; 中村 公則 北海道大学, 先端生命科学研究院, 准教授 (80381276)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 膵腸相関 / 膵がん / 自然免疫 / 腸内細菌叢 / 医食同源 / 膵癌 / 腸内細菌 / 悪性化 / 腸内環境

Outline of Final Research Achievements

The tumorigenic process of pancreatic ductal carcinoma (PDA) may be closely associated with homeostasis of the intestinal tract, e.g., innate immune system. To elucidate the "Pancreatic-Intestinal Crosstalk" during the tumor initiation, we analyzed the alterations in an intestinal environment using a mouse strain which spontaneously develops acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasias (PanINs), offering a model of the early-stage of the pancreatic tumorigenesis.
16S rRNA gene-based metagenomics assay of stool DNA provided a specific microflora profile during pancreatitis-induced progression from ADM into PanIN. Besides, the morphological study demonstrated the close link between the tumorigenic process in the pancreas and the intestinal tract where Paneth cells may play an essential role.

Research Products

• [Journal Article] GNAS drives pancreatic tumorigenesis via PKA-SIK signaling and reprogramming lipid metabolism (2018)
  • Author(s): Patra KC, Kato Y, Mizukami Y, Widholz S, Kottakis F, Boukhali M, Revenco I, Grossman EA, Liss AS, Screaton RA, Ryan DP, Mino-Kenudson M, Fernandez-del Castillo C, Nomura DK, Haas W, Bardeesy N.
  • Journal Title: Nature Cell Biology Volume: 印刷中
  • Peer Reviewed
• [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
• [Journal Article] Tracking the clonal evolution of adenosquamous carcinoma, a rare variant of intraductal papillary mucinous neoplasm of the pancreas. (2016)
  • Author(s): Matsuzaka S, Karasaki H, Ono Y, Ogata M, Oikawa K, Tamakawa S, Chiba S, Muraki M, Yokochi T, Funakoshi H, Kono T, Nagashima K, Mizukami Y.
  • Journal Title: Pancreas Volume: XX
  • Peer Reviewed
• [Journal Article] The protein expression level of Gli2 is a feasible marker of ligand-dependent hedgehog activation in pancreatic neoplasms. (2016)
  • Author(s): Sugiyama Y, Sasajima J, Mizukami Y, Koizumi K, Kawamoto T, Karasaki H, Yusuke Ono, Tanabe H, Fujiya M, Kohgo Y.
  • Journal Title: Pol J Pathol Volume: XX
  • Peer Reviewed
• [Journal Article] A Rare Case of Epidermoid Cyst in the Pancreatic Tail Invaginated from the Splenic Hilum: Long-term Alteration in Imaging Findings. (2016)
  • Author(s): Sugiyama Y, Kawamoto T, Sasajima J, Koizumi K, Karasaki H, Mizukami Y.
  • Journal Title: Internal Medicine Volume: XX
  • Peer Reviewed
• [Presentation] シンポジウム5;「今こそ変化の時。－精密医療のための患者個別アッセイモデルとソーシャルネットワーク－」 (2017)
  • Author(s): 水上裕輔
  • Organizer: 第30回日本動物実験代替法学会
• [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
• [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
• [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] digital PCR protocol to capture low-copy KRAS mutations in plasma cell-free DNA by pre-amplification (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 (2017)
  • Author(s): 水上裕輔
  • Organizer: 第15回日本臨床腫瘍学会学術総会
• [Presentation] Plasma DNA genotyping using digital PCR for early detection of pancreatic neoplasm (2015)
  • Author(s): Mizukami Y, Ono Y, Karasaki H, Ogata M, Koizumi K, Ando K, Yokochi T, Yamada M, Kono T, Nagashima K
  • Organizer: 6th Annual Meeting of the American Pancreatic Association
  • Place of Presentation: San Diego
  • Year and Date: 2015-11-04
  • Int'l Joint Research
• [Presentation] Plasma DNA genotyping using digital PCR for early detection of pancreatic cancer (2015)
  • Author(s): Mizukami Y, Ono Y, Karasaki H, Asahara S, Ando K, Shinohara T, Nagashima K
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] 液体生検による膵癌リスク評価 (2015)
  • Author(s): 水上裕輔、真口宏介、小泉一也
  • Organizer: 第23回日本消化器関連学会週間
  • Place of Presentation: 東京
  • Year and Date: 2015-10-08
• [Presentation] 小野裕介、唐崎秀則、千葉伸一、長嶋和郎、水上裕輔 (2015)
  • Author(s): 膵管内乳頭粘液性腫瘍より発生した膵腺扁平上皮癌
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08