Understanding mechanism of acidic pH induced tumor progression

• Project/Area Number: 16K14605
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: The University of Tokyo
• Principal Investigator: Osawa Tsuyoshi 東京大学, 先端科学技術研究センター, 特任准教授 (50567592)
• Co-Investigator(Renkei-kenkyūsha): SHIMAMURA Teppei 名古屋大学, 大学院医学系研究科, 特任准教授 (00623943) ; KANKI Yasuharu 東京大学, アイソトープ総合センター, 助教 (00534869) ; SHIRAISHI Yuichi 東京大学, 医科学研究所, 助教 (70516880)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: がん微小環境 / 低pH / がん代謝 / 転写・代謝制御 / 転写制御

Outline of Final Research Achievements

The tumor microenvironment plays an essential role in cancer progression, however, the mechanism of cancer progression induced by acidic pH microenvironment is still largely unknown. In this study, acidic pH cell culture system was established to identify the transcriptional-metabolic pathways for cancer progression under acidic pH tumor microenvironment.
As a result of this research, we established a simple model culture system to maintain acidic pH for at least 3 days and identified SREBP2 as a key transcriptional regulator under acidic pH using integration of comprehensive gene expression analysis and transcription factor motif analysis and we published our findings (Cell Reports, 2017).Moreover, accumulation and metabolic pathway specific to acidic pH are under investigation.

Research Products

• [Journal Article] Overexpression of p54nrb/NONO induces differential EPHA6 splicing and contributes to castration-resistant prostate cancer growth (2018)
  • Author(s): Yamamoto R, Osawa T, Sasaki Y, Yamamoto S, Anai M, Izumi K, Matsumura Y, Sakai J, Aburatani H, Mizokami A, Kodama T, Tanaka T
  • Journal Title: Oncotarget Volume: 9 Issue: 12 Pages: 10510-10524
  • DOI: 10.18632/oncotarget.24063
  • Peer Reviewed
• [Journal Article] Establishment of an extracellular acidic pH culture system (2017)
  • Author(s): Kondo A & Osawa T
  • Journal Title: J Vis Exp. Volume: 129 Issue: 129
  • DOI: 10.3791/56660
  • Peer Reviewed / Open Access
• [Journal Article] A subset of cerebrovascular pericytes originates from mature macrophages in the very early phase of vascular development in CNS. (2017)
  • Author(s): S. Yamamoto, M. Muramatsu, E. Azuma, M. Ikutani, Y. Nagai, H. Sagara, B.N. Koo, S. Kita, E. O’Donnell, T. Osawa, H. Takahashi, K.I. Takano, M. Dohmoto, M. Sugimori, I. Usui, Y. Watanabe, N. Hatakeyama, T. Iwamoto, I. Komuro, K. Takatsu, K. Tobe, S. Niida, N. Matsuda, M. Shibuya, M. Sasahara
  • Journal Title: Sci Rep Volume: 7：3855 Issue: 1 Pages: 1-16
  • DOI: 10.1038/s41598-017-03994-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long Noncoding RNA JHDM1D-AS1 Promotes Tumor Growth by Regulating Angiogenesis in Response to Nutrient Starvation (2017)
  • Author(s): Kondo A, Nonaka A, Shimamura T, Yamamoto S, Yoshida T, Kodama T, Aburatani H, Osawa T
  • Journal Title: Molecular and Cellular Biology Volume: 37 Issue: 18
  • DOI: 10.1128/mcb.00125-17
  • Peer Reviewed / Open Access
• [Journal Article] Dynamically and epigenetically coordinated GATA/ETS/SOX transcription is indispensable for endothelial cell differentiation (2017)
  • Author(s): Kanki Y, Nakaki R, Shimamura T, Matsunaga T, Yamamizu K, Katayama S, Suehiro JI, Osawa T, Aburatani H, Kodama T, Wada Y, Yamashita JK, Minami T.
  • Journal Title: Nucleic Acids Research Volume: 印刷中 Issue: 8 Pages: 4344-4358
  • DOI: 10.1093/nar/gkx159
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Extracellular Acidic pH Activates the Sterol Regulatory Element-binding Protein 2 to Promote Tumor Progression (2017)
  • Author(s): Kondo A, Yamamoto S, Nakaki R, Shimamura T, Hamakubo T, Sakai J, Kodama T, Yoshida T, Aburatani H and Osawa T
  • Journal Title: Cell Reports Volume: 18 Issue: 9 Pages: 2228-2242
  • DOI: 10.1016/j.celrep.2017.02.006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] がん代謝と血管生物学の融合を目指して (2017)
  • Author(s): 大澤毅ら
  • Organizer: 第３回血管生物若手研究会
  • Place of Presentation: 淡路夢舞台国際会議場（兵庫県）
  • Year and Date: 2017-03-03
  • Invited
• [Presentation] ニュートリオミクスから迫るがんの病態解明と治療戦略 (2017)
  • Author(s): 大澤 毅
  • Organizer: ConBio2017
  • Invited
• [Presentation] Down-regulation of PE Synthesis promotes tumor progression under starvation (2017)
  • Author(s): 大澤 毅
  • Organizer: 第７6回日本癌学会学術総会
• [Presentation] 腫瘍微小環境における細胞膜リン脂質代謝の役割 (2017)
  • Author(s): 大澤 毅
  • Organizer: 第5回がんと代謝研究会
  • Invited
• [Presentation] 栄養飢餓におけるがんのトランスメタボロミクス (2016)
  • Author(s): 大澤毅
  • Organizer: 第３９回日本分子生物学会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] Phosphoethanolamine Stimulates Cancer Cell Toerance against Nutrient Starvation through Alteration of PE Biosynthesis (2016)
  • Author(s): 大澤毅ら
  • Organizer: 第７５回日本癌学会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2016-10-06
• [Presentation] マルチオミクスが解き明かす腫瘍微小環境とがん代謝 (2016)
  • Author(s): 大澤毅
  • Organizer: 第８９回日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県）
  • Year and Date: 2016-09-25
  • Invited
• [Presentation] がん微小環境と代謝エピエノム制御の研究 (2016)
  • Author(s): 大澤毅
  • Organizer: 第２５回日本がん転移学会
  • Place of Presentation: 米子コンベンションセンター（鳥取県）
  • Year and Date: 2016-07-20
  • Invited
• [Presentation] 腫瘍微小環境から捉えたがんの代謝戦略 (2016)
  • Author(s): 大澤毅
  • Organizer: 第４回がんと代謝研究会
  • Place of Presentation: かごしま県民交流センター（鹿児島県）
  • Year and Date: 2016-07-07
  • Invited
• [Book] 「酢酸代謝」、実験医学 がん代謝ワールブルグを超えて全容解明に挑む (2017)
  • Author(s): 大澤 毅
  • Total Pages: 5
  • Publisher: 羊土社
• [Book] 遺伝子制御の新たな主役栄養シグナル (2017)
  • Author(s): 大澤毅
  • Total Pages: 6
  • Publisher: 羊土社
• [Remarks] 酸性環境における腫瘍の悪性化に コレステロール代謝制御タンパク質が寄与することを発見
  • URL: http://www.lsbm.org/news/2017/0301.html
• [Remarks] 酸性環境における腫瘍の悪性化に コレステロール代謝制御タンパク質が寄与することを発見
  • URL: http://www.genome.rcast.u-tokyo.ac.jp/wordpress/wp-content/uploads/2017/03/a62d8951728e5cf5ce0382c895756c61.pdf