PLEKHA5 as a Biomarker and Potential Mediator of Melanoma Brain Metastasis

Abstract

Purpose Approximately 40% of metastatic melanoma patients develop brain metastases. Our purpose was to identify genes aberrantly expressed in melanoma 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 versus parental A375P cells) and compared them to 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 vitro model of the blood brain barrier (BBB) was generated to evaluate potential mediators of brain metastases. Results PLEKHA5 was differentially expressed in both the A375 cell line model and patient samples subjected to gene expression profiling. At the protein level, by quantitative immunofluorescence, PLEKHA5 was associated with decreased brain metastasis free survival. PLEKHA5 over-expression was not associated with other metastatic sites. Knock-down of PLEKHA5 decreases 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 knock-down 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 extra-cerebral sites.

Stilbenoid‐Mediated Epigenetic Activation of Semaphorin 3A in Breast Cancer Cells Involves Changes in Dynamic Interactions of DNA with DNMT3A and NF1C Transcription Factor

“…Hypermethylated ITGA7 belongs to the integrin family and is a newly identified tumor suppressor gene that decreases migration and invasion of cancer cells . On the other hand, hypomethylated MMP1 is a potent oncogene promoting metastasis and multi‐drug resistance, and hypomethylated PLEKHA5 facilitates metastasis to the brain . Hence, the functional role of differential methylation within those genes in response to RSV is unclear.…”

Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites

“…This TMA has been previously described (23). Collection of specimens and clinical data was approved by a Yale University Institutional Review Board.…”

“…Age at diagnosis ranged from 20 to 79 (mean-55.4). Follow-up time was up to 187.65 months, mean-31.2 months (23). At diagnosis of stage IV disease, 13% had M1a disease, 29%-M1b and 58%-M1c.…”

The Microenvironmental Landscape of Brain Tumors

“…This phenomenon may indicate a type of ‘leukocytic mimicry’ through which metastatic cells could execute immune expression programs that promote cell migration and invasion. In other studies, additional factors have been identified as potential site-specific mediators of BBB transmigration, including PTGS2, HB-EGF, ST6GALNAC5 (Bos et al, 2009), PLEKHA5 (Jilaveanu et al, 2015), and the serum factor PLGF (Li et al, 2013). It is also becoming apparent that BBB integrity is heterogeneously affected within brain tumors (Lockman et al, 2010; Morikawa et al, 2015).…”