Vascular mimicry as a facilitator of melanoma brain metastasis.
Olivia K ProvanceVictor Oginga OriaThuy T TranJasmine I CaulfieldChristopher R ZitoAdam Aguirre-DuclerKurt A SchalperHarriet M KlugerLucia B JilaveanuPublished in: Cellular and molecular life sciences : CMLS (2024)
Melanoma has the highest propensity among solid tumors to metastasize to the brain. Melanoma brain metastases (MBM) are a leading cause of death in melanoma and affect 40-60% of patients with late-stage disease. 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 prognosis in many tumor types, but its significance in MBM remains poorly understood. We found that VM density is elevated in MBM compared to paired extracranial specimens and is associated with tumor volume and CNS edema. 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 inhibits VM and prolongs 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.
Keyphrases
- poor prognosis
- skin cancer
- end stage renal disease
- white matter
- small cell lung cancer
- resting state
- long non coding rna
- brain metastases
- gene expression
- basal cell carcinoma
- newly diagnosed
- type diabetes
- ejection fraction
- chronic kidney disease
- transcription factor
- cerebral ischemia
- physical activity
- single cell
- deep learning
- machine learning
- combination therapy
- adipose tissue
- patient reported outcomes
- electronic health record
- oxidative stress
- diabetic retinopathy
- vascular endothelial growth factor
- prognostic factors
- artificial intelligence
- ultrasound guided
- blood brain barrier
- subarachnoid hemorrhage
- peritoneal dialysis
- optical coherence tomography
- fine needle aspiration