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Thrombomodulin (TM), a type I transmembrane glycoprotein known for initiating sprouting angiogenesis, has been implicated in tumor vascularization. However, its role in melanoma progression and VM remains poorly characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>TM expression was evaluated in human cutaneous melanoma biopsies and an endothelial\u2013melanoma co-culture system. Functional assays were conducted to assess the impact of TM knockdown and overexpression on cell adhesion and VM formation. Domain-specific contributions of TM were investigated using constructs targeting its lectin-like domain and ezrin-binding motif. Mechanistic studies involved pharmacological inhibition of focal adhesion kinase (FAK) and siRNA-mediated silencing of ezrin. Therapeutic potential was assessed using a soluble TM lectin domain in both in vitro and in vivo melanoma models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>TM was expressed in both angiogenic and non-angiogenic vessels within melanoma tissues and co-culture systems. TM knockdown impaired cell adhesion and suppressed VM formation, while TM overexpression in TM-null melanoma cells enhanced cellular plasticity via its lectin-like domain and ezrin-binding motif. Inhibition of FAK or silencing of ezrin reversed the TM-induced phenotypic switch. Treatment with a soluble TM lectin domain reduced cancer cell plasticity in vitro and significantly inhibited melanoma tumor growth and metastasis in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>TM promotes melanoma cell plasticity and VM through FAK- and ezrin-dependent pathways. These findings position TM as a key regulator of tumor progression and suggest that targeting TM may offer a novel therapeutic strategy to disrupt cancer cell plasticity and suppress melanoma growth.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12929-026-01217-2","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T12:32:00Z","timestamp":1769517120000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thrombomodulin facilitates melanoma progression via FAK- and ezrin-mediated phenotypic plasticity"],"prefix":"10.1186","volume":"33","author":[{"given":"Cheng-Hsiang","family":"Kuo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ru-Han","family":"Sie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya-Chu","family":"Ku","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng-Lin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao-Kai","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao-Han","family":"Lai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua-Lin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"issue":"8","key":"1217_CR1","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1038\/s43018-023-00595-y","volume":"4","author":"A P\u00e9rez-Gonz\u00e1lez","year":"2023","unstructured":"P\u00e9rez-Gonz\u00e1lez A, B\u00e9vant K, Blanpain C. 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