Basic research on cancer therapy development targeting anchorage independence

• Project/Area Number: 15K06850
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: 防衛大学校(総合教育学群、人文社会科学群、応用科学群、電気情報学群及びシステム工学群)
• Principal Investigator: Uekita Takamasa 防衛大学校(総合教育学群、人文社会科学群、応用科学群、電気情報学群及びシステム工学群), 応用科学群, 准教授 (50373402)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 癌転移 / 足場非依存性 / シグナル伝達 / 複合体形成 / 低分子化合物 / CDCP1 / Src / PKCδ / がん転移 / 細胞運動能 / 浸潤 / 細胞内シグナル / 細胞死

Outline of Final Research Achievements

In order to target anchorage-independence, which is a majour function of cancer metastasis, as a target of cancer therapy, we aimed to clarify the control mechanism of anchorage-independence by CUB domain-containing protein 1 ( CDCP1). In this study, we revealed that the extracellular CUB2 domain of CDCP1 is involved in the CDCP1 homoohilic complex formation on the cell membrane and is also important for regulating CDCP1 signal via activation of Src family kinase. In addition, we identified two small-molecular compounds effective for suppressing anchorage-independence by blocking CDCP1 signal and succeeded in suppressing metastasis of gastric cancer cells by mouse peritoneal dissemination model.
These results suggest that CDCP1 is useful candidate for cancer therapy targeting anchorage-independence of cancer cells.

Research Products

• [Journal Article] The extracellular CUB domain of CDCP1 is involved in cell-cell contact and regulates collective cell migration in BxPC3 cells. (2018)
  • Author(s): Sawayama T, Uekita T
  • Journal Title: Memoir NDA Volume: 印刷中
  • Peer Reviewed
• [Journal Article] A Sensitive Microbead-Based Organic Media-Assisted Method for Proteomics Sample Preparation from Dilute and Denaturing Solutions (2017)
  • Author(s): Taoka Masato、Fujii Michihiko、Tsuchiya Masahiro、Uekita Takamasa、Ichimura Tohru
  • Journal Title: ACS Applied Materials & Interfaces Volume: 9 Issue: 49 Pages: 42661-42667
  • DOI: 10.1021/acsami.7b16095
  • Peer Reviewed
• [Journal Article] Novel small molecule inhibiting CDCP1-PKCδ pathway reduces tumor metastasis and proliferation. (2017)
  • Author(s): Nakashima K, Uekita T, Yano S, Kikuchi JI, Nakanishi R, Sakamoto N, Fukumoto K, Nomoto A, Kawamoto K, Shibahara T, Yamaguchi H, Sakai R.
  • Journal Title: Cancer Sci. Volume: 印刷中 Issue: 5 Pages: 1049-1057
  • DOI: 10.1111/cas.13218
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] TRIM32-Cytoplasmic-Body Formation Is an ATP-Consuming Process Stimulated by HSP70 in Cells. (2017)
  • Author(s): Kawaguchi Y, Taoka M, Takekiyo T, Uekita T, Shoji I, Hachiya N, Ichimura T.
  • Journal Title: PLoS One Volume: １２（１） Issue: 1 Pages: 1-5
  • DOI: 10.1371/journal.pone.0169436
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Augmentation of invadopodia formation in temozolomide-resistant or adopted glioma is regulated by c-Jun terminal kinase-paxillin axis (2015)
  • Author(s): Ueno H, Tomiyama A, Yamaguchi H, Uekita T et al.
  • Journal Title: Biochem Biophys Res Commun Volume: 468 Issue: 1-2 Pages: 240-247
  • DOI: 10.1016/j.bbrc.2015.10.122
  • Peer Reviewed
• [Presentation] Analysis of FAK-mediated anchorage-independent cell growth in small cell lung cancer. (2017)
  • Author(s): 上北尚正
  • Organizer: 第26回がん転移学会学術集会・総会
• [Presentation] Cleavage of CDCP1 regulates signaling of anchorage-independence through its homophilic complex formation. (2017)
  • Author(s): 澤山忠司、上北尚正
  • Organizer: 第26回がん転移学会学術集会・総会
• [Presentation] CDCP1細胞外ドメイン依存的な同種多量体形成を介した足場非依存性能の制御機構の解明 (2017)
  • Author(s): 澤山忠司、上北尚正
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] The possibility of CUB2 domain of CDCP1 extracellular domain as a novel therapeutic target for cancer metastasis. (2017)
  • Author(s): 澤山忠司、上北尚正
  • Organizer: CinBio 2017
• [Presentation] Homophilic complex formation of CDCP1 by CUB2 domain regulates lung cancer invasion. (2017)
  • Author(s): Sawayama T, Uekita T
  • Organizer: NCRI Cancer Conference 2017
  • Int'l Joint Research
• [Presentation] CDCP1細胞外ドメインによる同種多量体形成はSrcを活性化し肺がん転移を亢進する (2016)
  • Author(s): 澤山忠司、上北尚正
  • Organizer: 第39回分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] Dimerization of CDCP1 via extracellular domain regulates anchorage independence by activating Src signaling (2016)
  • Author(s): 澤山忠司、上北尚正
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06
• [Presentation] CDCP1細胞外ドメインによる同種2量体形成はSrcを活性化し癌の足場非依存性を制御する (2016)
  • Author(s): 澤山忠司、上北尚正
  • Organizer: 第25回日本がん転移学会学術集会・総会
  • Place of Presentation: 米子コンベンションセンター
  • Year and Date: 2016-07-21
• [Presentation] CDCP1細胞外ドメインは，同種多量体形成によってがん細胞の運動能を促進する。 (2015)
  • Author(s): 澤山忠司、上北尚正
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] CDCP1は細胞外ドメインによる同種複合体形成を介してがん細胞の運動能を制御する (2015)
  • Author(s): 澤山忠司、上北尚正
  • Organizer: 第７４回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] CDCP1細胞外ドメインは，同種２量体形成によってがん細胞の運動能を制御する。 (2015)
  • Author(s): 澤山忠司、上北尚正
  • Organizer: 第２４回日本がん転移学会学術集会/総会
  • Place of Presentation: シティプラザ大阪
  • Year and Date: 2015-07-23