Journal of biomedical science · 2026
Thrombomodulin facilitates melanoma progression via FAK- and ezrin-mediated phenotypic plasticity.
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Kuo Cheng-Hsiang, Sie Ru-Han, Ku Ya-Chu, Wu Cheng-Lin, Hsu Chao-Kai, Lai Chao-Han, Wu Hua-Lin
Аннотация
BACKGROUND: Cancer cell plasticity enables dynamic transitions between cellular states, contributing to tumor progression and the acquisition of phenotypic traits such as vascular mimicry (VM), which promotes malignancy and resistance to anti-angiogenic therapies. 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.
METHODS: TM expression was evaluated in human cutaneous melanoma biopsies and an endothelial-melanoma 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: TM expression was evaluated in human cutaneous melanoma biopsies and an endothelial-melanoma 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.
RESULTS: 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.
CONCLUSIONS: 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.