Melanoma cell adhesion molecule is the driving force behind the dissemination of melanoma upon S100A8/A9 binding in the original skin lesion. (28th June 2019)

• Record Type: Journal Article
• Authors: Chen, Youyi; Sumardika, I Wayan; Tomonobu, Nahoko; Winarsa Ruma, I Made; Kinoshita, Rie; Kondo, Eisaku; Inoue, Yusuke; Sato, Hiroki; Yamauchi, Akira; Murata, Hitoshi; Yamamoto, Ken-ichi; Tomida, Shuta; Shien, Kazuhiko; Yamamoto, Hiromasa; Soh, Junichi; Liu, Ming; Futami, Junichiro; Sasai, Kaori; Katayama, Hiroshi; Kubo, Miyoko; Putranto, Endy Widya; Hibino, Toshihiko; Sun, Bei; Nishibori, Masahiro; Toyooka, Shinichi; Sakaguchi, Masakiyo
• Is Part Of: Cancer letters. Volume 452(2019)
• Page Start: 178
• Page End: 190
• Publication Date: 2019-06-28
• Subjects: S100 protein -- Metastasis -- Inflammation -- Seed and soil hypothesis -- Matrix metalloproteinase; ETS E26 transformation specific -- ETV4 ETS translocation variant 4 -- MCAM melanoma cell adhesion molecule -- MMP25 matrix metalloproteinase-25 -- PEA3 polyoma enhancer activator 3 -- TPL2 tumor progression locus 2; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.03.023
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Since metastasis accounts for the majority of cancer-associated deaths, studies on the mechanisms of metastasis are needed to establish innovative strategies for cancer treatment. We previously reported that melanoma cell adhesion molecule (MCAM) functions as a critical receptor for S100A8/A9, and binding of S100A8/A9 to MCAM results in the migration of melanoma cells to lung tissue. However, the critical role of MCAM in the original melanoma skin lesion is still not clear. In this study, we aimed to determine the importance of the S100A8/A9-MCAM axis in melanoma dissemination in a skin lesion as a critical early step for metastasis. Mechanistic studies revealed the downstream signaling of MCAM that signaled the induction of metastasis. S100A8/A9-MCAM binding activates mitogen-activated protein kinase kinase kinase 8 (MAP3K8), also termed TPL2, leading to strong activation of the transcription factor ETV4 and subsequent induction of matrix metalloproteinase-25 (MMP25), and finally to induction of melanoma lung tropic metastasis. Collectively, our results demonstrate a crucial role of the S100A8/A9-MCAM signaling axis in metastatic onset of melanoma cells and indicate that strategies targeting the identified pathway may be useful for the establishment of innovative anti-cancer therapies. Highlights: S100A8/A9 binding to MCAM promotes melanoma dissemination. ETV4 is a key transcription factor downstream of MCAM. MCAM-mediated cancer dissemination requires the TPL2-ETV4-MMP25 pathway. High-level MMP25 is associated with melanoma progression.