Identification of molecular mechanisms that regulate the proliferation-migration dichotomy of cancer cells

• Project/Area Number: 18H02638
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Nagoya University
• Principal Investigator: Enomoto Atsushi 名古屋大学, 医学系研究科, 教授 (20432255)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2020: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
• Keywords: 細胞遊走 / 増殖・遊走ダイコトミー / Girdin / 代謝 / 細胞周期 / 放射線療法 / DNA障害 / 細胞移動 / CD98 / 細胞運動

Outline of Final Research Achievements

The actin-binding protein Girdin is a regulator of migration of neuroblasts and cancer cells. The present study revealed that Girdin regulates the localization of the amino acid transporter complex (CD98 complex) to control the activity of mTORC1, a master regulator of cell metabolism and proliferation. We also showed the involvement of Girdin in the sensitivity of cancer cells to ulatraviolet C. These findings suggest that Girdin is involved in various processes of cancer cells including migration and metabolism and sensitivity to radiation therapies.

Academic Significance and Societal Importance of the Research Achievements

Girdin分子は以前の研究により増殖・遊走ダイコトミーの制御因子の一つであるとされていたが、今回の研究により同分子の機能多様性が明らかとなった。生体内のがん細胞も浸潤期には分裂しないことが提唱されており（stop or go hypothesis）、抗がん剤に対する抵抗性の原因とされている。今後、Girdinの多様な制御をコントロールできる手法が解明されれば、新規治療法の開発の端緒となる可能性がある。

Research Products

• [Journal Article] Oncolytic activity of naturally attenuated herpes-simplex virus HF10 against an immunocompetent model of oral carcinoma (2021)
  • Author(s): Takano G, Esaki S, Goshima F, Enomoto A, Hatano Y, Ozaki H, Watanabe T, Sato Y, Kawakita D, Murakami S, Murata T, Nishiyama Y, Iwasaki S, Kimura H
  • Journal Title: Molecular Therapy - Oncolytics Volume: 20 Pages: 220-227
  • DOI: 10.1016/j.omto.2020.12.007
  • Peer Reviewed / Open Access
• [Journal Article] The balance of stromal BMP signaling mediated by GREM1 and ISLR drives colorectal carcinogenesis. (2021)
  • Author(s): Kobayashi H, Gieniec KA, Wright JA, Wang T, Asai N, Mizutani Y, Iida T, Ando R, Suzuki N, Lannagan TR, Ng JQ, Hara A, Shiraki Y, Mii S (14番目/36人中), ..., Enomoto A, Takahashi M, Worthley DL, Woods SL.
  • Journal Title: Gastroenterology Volume: 160 Pages: 1224-1239
  • DOI: 10.1053/j.gastro.2020.11.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-β signaling. (2020)
  • Author(s): Taki T, Shiraki Y, Enomoto A, Weng L, Chen C, Asai N, Murakumo Y, Yokoi K, Takahashi M, Mii S.
  • Journal Title: Cancer Science Volume: 111 Pages: 4616-4628
  • DOI: 10.1111/cas.14673
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Complex roles of the actin-binding protein Girdin/GIV in DNA damage-induced apoptosis of cancer cells. (2020)
  • Author(s): Chen C, Enomoto A, Weng L, Taki T, Shiraki Y, Mii S, Ichihara R, Kanda M, Koike M, Kodera Y, Takahashi M.
  • Journal Title: Cancer Sci Volume: 111 Pages: 4303-4317
  • DOI: 10.1111/cas.14637
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cancer-associated fibroblasts that restrain cancer progression: Hypotheses and perspectives (2020)
  • Author(s): Miyai Y, Esaki N, Takahashi M, Enomoto A
  • Journal Title: Cancer Science Volume: 111 Pages: 1047-1057
  • DOI: 10.1111/cas.14346
  • Peer Reviewed / Open Access
• [Journal Article] Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis. (2019)
  • Author(s): Mizutani Y, Kobayashi H, Iida T, Asai N, Masamune A, Hara A, Yamaguchi J, Wang T, Woods SL, Worthley D, Shimamura T, Fujishiro M, Hirooka Y, Enomoto A, Takahashi M. et al.
  • Journal Title: Cancer Res Volume: 79 Pages: 5367-5381
  • DOI: 10.1158/0008-5472.can-19-0454
  • NAID: 120006786261
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin in Cardiac Tissue Repair and the Development of Diastolic Dysfunction. (2019)
  • Author(s): Hara A, Kobayashi H, Asai N1, Saito S, Higuchi T, Kato K, Okumura T, Bando YK, Takefuji M, Mizutani Y, Miyai Y, Saito S, Maruyama S, Maeda K, Ouchi N, Nagasaka A, Miyata T, Mii S, Kioka N, Worthley DL, Murohara T, Takahashi M, Enomoto A
  • Journal Title: Circ Res. Volume: 125 Issue: 4 Pages: 414-430
  • DOI: 10.1161/circresaha.119.314806
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cancer-associated fibroblasts in gastrointestinal cancer (2019)
  • Author(s): Kobayashi H, Enomoto A, Woods SL, Burt AD, Takahashi M, Worthley DL
  • Journal Title: Nature Reviews Gastroenterology & Hepatology Volume: 16 Pages: 282-295
  • DOI: 10.1038/s41575-019-0115-0
  • NAID: 120006711433
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Negative regulation of amino acid signaling by MAPK-regulated 4F2hc/Girdin complex (2018)
  • Author(s): Liang Weng , Yi-Peng Han, Atsushi Enomoto, Yasuyuki Kitaura, Shushi Nagamori, Yoshikatsu Kanai, Naoya Asai, Jian An, Maki Takagishi, Masato Asai, Shinji Mii, Takashi Masuko, Yoshiharu Shimomura, Masahide Takahashi.
  • Journal Title: Plos Biology Volume: 16
  • DOI: 10.1371/journal.pbio.2005090
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Essential Role of Linx/Islr2 in the Development of the Forebrain Anterior Commissure. (2018)
  • Author(s): Abudureyimu S, Asai N, Enomoto A, Weng L, Kobayashi H, Wang X, Chen C, Mii S, Takahashi M.
  • Journal Title: Sci Rep. Volume: 8 Pages: 7292-7292
  • DOI: 10.1038/s41598-018-24064-0
  • Open Access
• [Journal Article] CD109 deficiency induces osteopenia with an osteoporosis-like phenotype in vivo. (2018)
  • Author(s): Mii S, Hoshino A, Enomoto A, Murakumo Y, Ito M, Yamaguchi A, Takahashi M.
  • Journal Title: Genes Cells Volume: 23 Pages: 590-598
  • DOI: 10.1111/gtc.12593
  • Peer Reviewed
• [Presentation] がん細胞のDNA損傷依存性細胞死におけるアクチン結合分子Girdinの役割 (2020)
  • Author(s): 榎本篤, Chen Chen, 滝哲郎, 高橋雅英.
  • Organizer: 第109回日本病理学会総会
• [Presentation] Stromal biology of cancer and its relevance in developing new anticancer therapeutics. (2020)
  • Author(s): Atsushi Enomoto
  • Organizer: 第79回日本癌学会学術総会
  • Invited
• [Presentation] Identification of cancer-associated fibroblasts that suppress pancreatic cancer progression (2019)
  • Author(s): Atsushi Enomoto, Yasuyuki Mizutani, Hiroki Kobayashi, Tadashi Iida, Susan L. Woods, Daniel L. Worthley, Masahide Takahashi
  • Organizer: American Association for Cancer Research (AACR) Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] Cancer-restraining cancer-associated fibroblasts and their roles in tumor progression and immunity (2019)
  • Author(s): Atsushi Enomoto
  • Organizer: Korean Cancer Association, 45th Annual Meeting and 5th International Cancer Conference
  • Int'l Joint Research / Invited
• [Presentation] Heterogeneity of cancer-associated fibroblasts and its significance in tumor progression and response to thrapies. (2018)
  • Author(s): Enomoto, A, Takahashi, M.
  • Organizer: The 6th JCA-AACR Special Joint Conference
  • Int'l Joint Research / Invited