Mechanisms of perivascular melanoma dispersal and survival in the brain

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PROJECT SUMMARY/ABSTRACT 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 patients. 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 challenge. 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 cortex. While this vascular co-optive growth pattern has been associated with poor survival in melanoma metastasis, vascular-mediated mechanisms are poorly understood and represents a unique opportunity to target the cohesive interactions between melanoma cells and the endothelium to prevent or treat brain metastases. My preliminary data has uncovered a vascular-mediated induction of transforming growth factor beta (TGFβ) and platelet-derived growth factor receptor beta (PDGFRβ) in melanoma cells after contact with brain endothelial cells. Additionally, this TGFβ-PDGFRβ signaling axis can activate the downstream PI3K/AKT pathway, which has sustained activation when the tumor suppressor phosphatase tensin homolog (PTEN) is lost. PI3K/AKT activation or loss of PTEN has been strongly implicated in the pathogenesis of melanoma brain metastases but has not been explored in the context of vascular-mediated survival or invasion. Thus, in my proposal I hypothesize that vascular-mediated induction of TGFβ-PDGFRβ signaling in concert with PTEN loss is important for melanoma cell invasion and survival in the brain microenvironment. Throughout my proposal, I will generate and utilize isogenic lines with alterations in TGFβ, PDGFRβ, or PTEN (or combinations of alterations) and will study their effects on migration and apoptosis through a variety of in vitro co-culture systems, ex vivo brain slice, and in vivo intracranial models. Successful completion of this work will reveal a novel vascular-derived role for TGFβ, PDGFRβ, and PTEN in melanoma brain metastasis; this will provide crucial insights and rationale for the development of therapeutics that disrupt cohesive interactions with the brain endothelium and exploit the survival advantages of the perivascular brain niche. To complete my goals, I have assembled a team of mentors with diverse but complementary fields of study to support my proposal. These include Drs. Andrew Dudley (tumor microenvironment/angiogenesis), Craig Slingluff (melanoma clinician-scientist), Camilo Fadul (brain metastasis clinician), James Mandell (neuropathologist), Roger Abounader (PTEN biology and brain cancers), David Kashatus (collaborator for the development of quantitative imaging platform of vessel co-option in the brain), and Hui Zong (advanced imaging and rodent models of brain cancers).