Poster Presentation 35th Lorne Cancer Conference 2023

Mechanisms of perivascular melanoma dispersal and survival in the brain (#349)

Sarah Wang 1 , Caroline P Riedstra 1 , Yu Zhang 1 , Andrew C Dudley 1 2
  1. Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, United States
  2. Comprehensive Cancer Center, University of Virginia, Charlottesville, VA, USA

Malignant melanoma has an unusually high propensity to metastasize to the brain; among stage IV patients 40-50% will develop clinically detectable intracranial disease, while on autopsy brain metastases can be detected in over 70% of patients1. Additionally, melanoma brain metastases are a marker of poor prognosis and despite improvements with systemic targeted therapies and immunotherapies, intracranial control still remains a significant challenge1. In the brain microenvironment, melanoma cells are found predominantly in a perivascular niche where they “co-opt” the vasculature to support their survival and invasion deep into the cortex2-5. Vascular co-optive growth is associated with poor survival in melanoma metastasis, but the molecular mechanisms that drive and sustain vessel co-option are poorly understood and represents a unique opportunity to target the cohesive interactions between melanoma cells and the endothelium to prevent or treat brain metastases6-8. My preliminary data has uncovered a vascular-mediated induction of transforming growth factor beta (TGFβ) and AKT activation in melanoma cells after contact with brain endothelial cells. Since PI3K/AKT activation or loss of phosphatase tensin homolog (PTEN), the negative regulator of AKT, has been strongly implicated in the pathogenesis of melanoma brain metastases, we hypothesize that vascular-induced TGFβ preferentially enhances survival and perivascular invasion of PTEN-null melanoma. Disrupting the cohesive contacts between brain-resident melanoma cells and the vasculature could reduce brain colonization and prevent perivascular dispersal throughout the brain.

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