Abstract
Melanoma has the highest propensity among solid tumors to metastasize to the brain.Melanoma brainmetastases (MBM) are a leading cause of deathinmelanoma and affect 40-60% of patients with late-stagedisease.Therefore, uncovering the molecular mechanisms behind MBM is necessary to enhance therapeutic interventions.Vascular mimicry (VM) is a form of neovascularization linked to invasion, increased risk of metastasis, and poor prognosisin many tumor types, but its significance in MBM remains poorly understood.We found that VM density is elevated in MBM comparedto pairedextracranialspecimensand is associated with tumor volume andCNSedema. In addition, our studies indicate a relevant role of YAP and TAZ, two transcriptional co-factors scarcely studied in melanoma, in tumor cell-vasculogenesis and in brain metastasis. We recently demonstrated activation of the Hippo tumor suppressor pathway and increased degradation of its downstream targets YAP and TAZ in a metastasis impaired cell line model.In the current study we establish the utility of anti-YAP/TAZ therapy in mouse models of metastatic melanoma whereby treatment effectively inhibitsVM andprolongs survival of mice with MBM. The data presented herein suggest that VM may be an important and targetable mechanism in melanoma and that VM inhibition might be useful for treating MBM, an area of high unmet clinical need, thus having important implications for future treatment regimens for these patients.
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