Biology of Human Tumors PLEKHA5 as a Biomarker and Potential Mediator of Melanoma Brain Metastasis

Purpose: Approximately 40% of patients with metastatic melanoma develop brain metastases. Our purpose was to identify genes aberrantly expressed inmelanoma that might be associated with propensity for brain homing. Experimental Design:We studied gene expression profiles in a cell line model of brain metastasis (cerebrotropic A375Br cells vs. parental A375P cells) and compared them with profiles of patients who developed early brain metastases and who did not. A tissue microarray containing 169 metastatic melanoma cases with variable time to brain metastasis was constructed to further study marker expression by quantitative immunofluorescence. An in vitromodel of the blood brain barrier (BBB) was generated to evaluate potential mediators of brain metastases. Results:PLEKHA5wasdifferentially expressed inboth theA375 cell line model and patient samples subjected to gene expression profiling. At the protein level, by quantitative immunofluorescence, PLEKHA5 was associated with decreased brain metastasisfree survival. PLEKHA5 overexpression was not associated with other metastatic sites. Knockdown of PLEKHA5 decreases the viability of A375Br cells, inhibits BBB transmigration and invasion in vitro. Similar results were found with YUMUL cells, cultured from a patient with overwhelming brain metastases. PLEKHA5 knockdown did not affect the viability of A375P cells. Conclusions: PLEKHA5 expression in melanoma tumors was associated with early development of brain metastases. Inhibition of PLEKHA5 might decrease passage across the BBB and decrease proliferation and survival of melanoma cells both in the brain and in extracerebral sites. Clin Cancer Res; 21(9); 1–10. 2014 AACR. See related commentary by Eisele et al., p. 1978