Clarification of endothelium activating mechanism regulated by AKAP12 and therapeutic application for metastasis

• Project/Area Number: 17K15622
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Kumamoto University
• Principal Investigator: Muramatsu Masashi 熊本大学, 生命資源研究・支援センター, 助教 (50568946)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 転移抑制遺伝子 / 血行性転移 / 血管内皮細胞 / 接着分子発現機構 / 線維芽細胞 / SASP / 腫瘍生物学

Outline of Final Research Achievements

AKAP12 controls Src signaling through direct scaffolding activity. AKAP12 is downregulated in the metastases of many human cancer types, and AKAP12-null mice (KO) are metastasis-prone. Here, we show that lung metastasis formation by mouse melanoma cells is 9-fold higher in syngeneic KO compared to WT hosts. Although melanoma cells adhered equally to KO or WT lung fibroblasts (LF), co-injection of melanoma cells with KO-LF increased lung metastasis at foci of activated endothelium. Increased melanoma adhesion on KO lung endothelial cells (LEC) was facilitated by increased E-Selectin and enhanced by VEGF from KO-LF. Finally, the ability of AKAP12 to attenuate Stat3 activation in KO-LF required its Src-scaffolding domain. Taken together, these data suggest that AKAP12 normally suppresses metastatic colonization by attenuating the expression of Selectin in local endothelial cells and VEGF secreted by neighboring fibroblasts in an AKAP12-regulated, Src/Stat3-dependent manner.

Academic Significance and Societal Importance of the Research Achievements

転移には血液中のがん細胞が活性化した血管内皮細胞に接着することが必須である。一方、AKAP12は時空間的に細胞内シグナルを調節する。本研究では、患者の転移組織において認められるAKAP12の発現低下と転移促進の関係性を、様々な実験モデルを用いて検証した。その結果、AKAP12の欠損は「血管内皮細胞上の接着分子発現誘導」と「線維芽細胞の細胞老化性分泌による血管内皮細胞の活性化」を介して転移を促進することを明らかにした。これはAKAP12の転移先臓器における新規機能を明らかにしただけでなく、このメカニズムを標的とする新しい転移治療法の開発に繋がる基盤的研究成果になることが期待される。

Research Products

• [Journal Article] Loss of Endogenous HMGB2 Promotes Cardiac Dysfunction and Pressure Overload-Induced Heart Failure in Mice (2019)
  • Author(s): Sato M, Miyata K, Tian Z, Kadomatsu T, Ujihara Y, Morinaga J, Horiguchi H, Endo M, Zhao J, Zhu S, Sugizaki T, Igata K, Muramatsu M, Minami T, Ito T, Bianchi ME, Mohri S, Araki K, Node K, Oike Y
  • Journal Title: Circulation Journal Volume: 83 Issue: 2 Pages: 368-378
  • DOI: 10.1253/circj.CJ-18-0925
  • NAID: 130007557092
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2019-01-25
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SSeCKS/Akap12 suppresses metastatic melanoma lung colonization by attenuating Src-mediated pre-metastatic niche crosstalk (2018)
  • Author(s): Muramatsu Masashi、Akakura Shin、Gao Lingqiu、Peresie Jennifer、Balderman Benjamin、Gelman Irwin H.
  • Journal Title: Oncotarget Volume: 9 Issue: 71 Pages: 33515-33527
  • DOI: 10.18632/oncotarget.26067
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Defensive effect of microRNA-200b/c against amyloid-beta peptide-induced toxicity in Alzheimer's disease models (2018)
  • Author(s): Higaki Sayuri、Muramatsu Masashi、Matsuda Akio、Matsumoto Kenji、Satoh Jun-ichi、Michikawa Makoto、Niida Shumpei
  • Journal Title: PLOS ONE Volume: 13 Issue: 5 Pages: e0196929-e0196929
  • DOI: 10.1371/journal.pone.0196929
  • 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] SSeCKS/AKAP12 scaffolding functions suppress B16F10-induced peritoneal metastasis by attenuating CXCL9/10 secretion by resident fibroblasts. (2017)
  • Author(s): Muramatsu M, Gao L, Peresie J, Balderman B, Akakura S, Gelman IH.
  • Journal Title: Oncotarget Volume: 8 Issue: 41 Pages: 70281-70298
  • DOI: 10.18632/oncotarget.20092
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Down Syndrome Critical Region (DSCR)-1 in endothelial cells controls tumor angiogenesis and pulmonary tumor metastasis (2018)
  • Author(s): 村松昌
  • Organizer: 日本癌学会学術総会
• [Presentation] NFAT-DSCR-1 signal regulates vascular integrity (2018)
  • Author(s): Muramatsu Masashi
  • Organizer: 16th Korea-Japan Joint Symposium of Vascular Biology
  • Int'l Joint Research
• [Presentation] AKAP12 scaffolding functions suppress peritoneal metastasis by attenuating CXCL10 secretion by resident fibroblasts (2017)
  • Author(s): Masashi Muramatsu
  • Organizer: 日本癌学会
• [Remarks] 熊本大学生命資源研究・支援センター分子血管制御分野HP
  • URL: http://irda-vascular.kuma-u.jp/
• [Remarks] 熊本大学薬学部/大学院薬学教育部 受賞・活動歴
  • URL: http://www.pharm.kumamoto-u.ac.jp/awards_activities/