The functional role of chromatin regulator in established PDAC

• Project/Area Number: 19H03639
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kyoto University
• Principal Investigator: Fukuda Akihisa 京都大学, 医学研究科, 講師 (70644897)
• Co-Investigator(Kenkyū-buntansha): 妹尾 浩 京都大学, 医学研究科, 教授 (90335266)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2022: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 膵癌 / 分子機序 / クロマチンリモデリング因子 / 膵がん / マウスモデル / 治療標的 / 治療 / エピジェネティクス / クロマチンリモデリング

Outline of Research at the Start

膵癌は最難治性癌であり、新規治療法の開発は急務の課題である。申請者らは、SWI/SNFクロマチンリモデリング複合体の必須因子BRG1に以前より着眼し、膵癌形成におけるBRG1の役割を世界に先駆けて明らかにしてきた。本研究では、一連の研究成果を踏まえ、独自の遺伝子改変膵癌モデルマウスを用いて、BRG1を標的とした新規膵癌治療法の開発に向けて、浸潤性膵癌の維持・進行におけるBRG1の機能的役割とその分子機構を解明する。

Outline of Final Research Achievements

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses among all human malignancies. It is urgently needed to develop novel therapeutic approaches for this lethal disease. We previously reported that BRG1/SOX9 axis is required for PDAC formation in mice and that BRG1 is expressed in approximately 80 % of human PDAC. In this study, we aimed to clarify the functional role of Brg1 in established PDAC in mice using a dual recombinase system and in human PDAC cells. We found that ①Brg1 knockout (KO) in established PDAC leads to increased apoptosis and reduced growth in mice. ②BRG1 is required for metastasis of PDAC cells in mice. ③Brg1 plays a critical role for cancer stemness of PDAC cells. ③ BRG1 knockdown (KD) or KO leads to increased apoptosis and decreased cell growth in human PDAC cells in vitro and in vivo. These data indicate that Brg1 could be a novel therapeutic target for PDAC.

Academic Significance and Societal Importance of the Research Achievements

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses among all human malignancies. It is urgently needed to develop novel therapeutic approaches for this lethal disease. This study revealed that Brg1 is required for established PDAC and could be a novel therapeutic target for PDAC.

Research Products

• [Journal Article] p53 protects against formation of extrahepatic biliary precancerous lesions in the context of oncogenic Kras. (2023)
  • Author(s): Munemasa Nagao, Kenta Mizukoshi, Shinnosuke Nakayama, Mio Namikawa, Yukiko Hiramatsu, Takahisa Maruno, Yuki Nakanishi, Tatsuaki Tsuruyama, Akihisa Fukuda*, Hiroshi Seno. *corresponding author
  • Journal Title: Oncotarget Volume: in press
  • Peer Reviewed
• [Journal Article] Concurrent activation of Kras and canonical Wnt signaling induces premalignant lesions that progress to extrahepatic biliary cancer in mice (2022)
  • Author(s): Nagao M, Fukuda A, Omatsu M, Namikawa M, Sono M, Fukunaga Y, Masuda T, Araki O, Yoshikawa T, Ogawa S, Masuo K, Goto N, Hiramatsu Y, Muta Y, Tsuda M, Maruno T, Nakanishi Y, Taketo MM, Ferrer J, Tsuruyama T, Nakanuma Y, Taura K, Uemoto S, Seno H.
  • Journal Title: Cancer Res. Volume: - Issue: 9 Pages: 1803-1817
  • DOI: 10.1158/0008-5472.can-21-2176
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of Arid1a and Pten in Pancreatic Ductal Cells Induces Intraductal Tubulopapillary Neoplasm via the YAP/TAZ Pathway. (2022)
  • Author(s): Fukunaga Y, Fukuda A, Omatsu M, Namikawa M, Sono M, Masuda T, Araki O, Nagao M, Yoshikawa T, Ogawa S, Hiramatsu Y, Muta Y, Tsuda M, Maruno T, Nakanishi Y, Ferrer J, Tsuruyama T, Masui T, Hatano E, Seno H.
  • Journal Title: Gastroenterology. Volume: 163 Issue: 2 Pages: 466-480
  • DOI: 10.1053/j.gastro.2022.04.020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Context-Dependent Roles of Hes1 in the Adult Pancreas and Pancreatic Tumor Formation. (2022)
  • Author(s): Marui S, Nishikawa Y, Shiokawa M, Yokode M, Matsumoto S, Muramoto Y, Ota S, Nakamura T, Yoshida H, Okada H, Kuwada T, Matsumori T, Kuriyama K, Fukuda A, Saur D, Aoi T, Uza N, Kodama Y, Chiba T, Seno H.
  • Journal Title: Gastroenterology. Volume: 163 Issue: 6 Pages: 1613-1629
  • DOI: 10.1053/j.gastro.2022.08.048
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] <scp>JNK</scp> pathway plays a critical role for expansion of human colorectal cancer in the context of <scp>BRG1</scp> suppression (2022)
  • Author(s): Yoshikawa Takaaki、Fukuda Akihisa、Omatsu Mayuki、Namikawa Mio、Sono Makoto、Fukunaga Yuichi、Masuda Tomonori、Araki Osamu、Nagao Munemasa、Ogawa Satoshi、Masuo Kenji、Goto Norihiro、Hiramatsu Yukiko、Muta Yu、Tsuda Motoyuki、Maruno Takahisa、Nakanishi Yuki、Kawada Kenji、Takaishi Shigeo、Seno Hiroshi
  • Journal Title: Cancer Science Volume: 113 Issue: 10 Pages: 3417-3427
  • DOI: 10.1111/cas.15520
  • Peer Reviewed / Open Access
• [Journal Article] Impact of neoadjuvant intensity-modulated radiation therapy on borderline resectable pancreatic cancer with arterial abutment; a prospective, open-label, phase II study in a single institution. (2022)
  • Author(s): Masui T, Nagai K, Anazawa T, Sato A, Uchida Y, Nakano K, Yogo A, Kaneda A, Nakamura N, Yoshimura M, Mizowaki T, Uza N, Fukuda A, Matsumoto S, Kanai M, Isoda H, Mizumoto M, Seo S, Hata K, Taura K, Kawaguchi Y, Takaori K, Uemoto S, Hatano E.
  • Journal Title: BMC Cancer Volume: 29 Issue: 1 Pages: 119-119
  • DOI: 10.1186/s12885-022-09244-6
  • Peer Reviewed
• [Journal Article] SNAIL2 contributes to tumorigenicity and chemotherapy resistance in pancreatic cancer by regulating IGFBP2 (2021)
  • Author(s): Masuo K, Chen R, Yogo A, Sugiyama A, Fukuda A, Masui T, Uemoto S, Seno H, Takaishi S.
  • Journal Title: Cancer Sci. Volume: 112 Issue: 12 Pages: 4987-4999
  • DOI: 10.1111/cas.15162
  • Peer Reviewed / Open Access
• [Journal Article] Brg1 is required to maintain colorectal cancer stem cells. (2021)
  • Author(s): Yoshikawa T, Fukuda A*, Omatsu M, Namikawa M, Sono M, Fukunaga Y, Masuda T, Araki O, Nagao M, Ogawa S, Masuo K, Goto N, Hiramatsu Y, Muta Y, Tsuda M, Maruno T, Nakanishi Y, Kawada K, Takaishi S, Seno H.
  • Journal Title: J Pathology Volume: 255 Pages: 257-269
  • Peer Reviewed
• [Journal Article] Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging (2021)
  • Author(s): Maruno Takahisa、Fukuda Akihisa、Goto Norihiro、Tsuda Motoyuki、Ikuta Kozo、Hiramatsu Yukiko、Ogawa Satoshi、Nakanishi Yuki、Yamaga Yuichi、Yoshioka Takuto、Takaori Kyoichi、Uemoto Shinji、Saur Dieter、Chiba Tsutomu、Seno Hiroshi
  • Journal Title: eLife Volume: 10 Pages: 1-24
  • DOI: 10.7554/elife.55117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The role of SWI/SNF chromatin remodeling complex in pancreatic cancer. *corresponding author (2021)
  • Author(s): 2.Motoyuki Tsuda, Akihisa Fukuda, Munenori Kawai, Osamu Araki, Hiroshi Seno.
  • Journal Title: Cancer Science Volume: 112 Issue: 2 Pages: 490-497
  • DOI: 10.1111/cas.14768
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Setdb1 inhibits p53-mediated apoptosis and is required for formation of pancreatic ductal adenocarcinomas in mice. (2020)
  • Author(s): 6.Ogawa S, Fukuda A, Matsumoto Y, Hanyu Yu, Sono M, Fukunaga Y, Masuda T, Araki O, Nagao M, Yoshikawa T, Goto N, Hiramatsu Y, Tsuda M, Maruno T, Nakanishii Y, Hussein S.M, Tsuruyama T, Takaori K, Uemotoio S, Seno H.
  • Journal Title: Gastroenterology Volume: 159 Issue: 2 Pages: 682-696
  • DOI: 10.1053/j.gastro.2020.04.047
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Insights into initiation and progression of PDAC. (2022)
  • Author(s): Akihisa Fukuda
  • Organizer: American Pancreatic Association Annual meeting
  • Int'l Joint Research / Invited
• [Presentation] Simultaneous loss of Arid1a and Pten in pancreatic ductal cells induces ITPN and PDAC through activation of the YAP/TAZ pathway. (2022)
  • Author(s): 福田晃久
  • Organizer: ムーンショット ワークショップ
  • Invited
• [Presentation] 膵がんの上皮間葉転換・転移の制御因子 (2022)
  • Author(s): 福田晃久、妹尾浩.
  • Organizer: 第3回「医学と数理」ワークショップ
  • Invited
• [Presentation] The role of chromatin remodeling regulators in pancreatic cancer. (2022)
  • Author(s): Akihisa Fukuda
  • Organizer: The 7th JCA-AACR Special Joint Conference
  • Int'l Joint Research / Invited
• [Presentation] クロマチン制御因子を標的とした新規膵がん治療法の開発. (2022)
  • Author(s): 福田晃久
  • Organizer: 京都大学「医学領域」産学連携推進機構／一般社団法人芝蘭会産学情報交流会セミナー
  • Invited
• [Presentation] The mechanism of pancreatic cancer development. (2021)
  • Author(s): Akihisa Fukuda
  • Organizer: The 5th Annual conference of Al-Azhar Hepatogastroenterology club (AHC, 2021), Therapeutic advances in hepatogastroenterology.
  • Int'l Joint Research / Invited