Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature

Abstract

The molecular biology of metastatic potential in melanoma has been studied many times previously and changes in the expression of many genes have been linked to metastatic behaviour. What is lacking is a systematic characterization of the regulatory relationships between genes whose expression is related to metastatic potential. Such a characterization would produce a molecular taxonomy for melanoma which could feasibly be used to identify epigenetic mechanisms behind changes in metastatic behaviour. To achieve this we carried out three separate DNA microarray analyses on a total of 86 cultures of melanoma. Significantly, multiple testing correction revealed that previous reports describing correlations of gene expression with activating mutations in BRAF or NRAS were incorrect and that no gene expression patterns correlate with the mutation status of these MAPK pathway components. Instead, we identified three different sample cohorts (A, B and C) and found that these cohorts represent melanoma groups of differing metastatic potential. Cohorts A and B were susceptible to transforming growth factor-beta (TGFbeta)-mediated inhibition of proliferation and had low motility. Cohort C was resistant to TGFbeta and demonstrated high motility. Meta-analysis of the data against previous studies linking gene expression and phenotype confirmed that cohorts A and C represent transcription signatures of weakly and strongly metastatic melanomas, respectively. Gene expression co-regulation suggested that signalling via TGFbeta-type and Wnt/beta-catenin pathways underwent considerable change between cohorts. These results suggest a model for the transition from weakly to strongly metastatic melanomas in which TGFbeta-type signalling upregulates genes expressing vasculogenic/extracellular matrix remodelling factors and Wnt signal inhibitors, coinciding with a downregulation of genes downstream of Wnt signalling.

V600E BRAF is associated with disabled feedback inhibition of RAF–MEK signaling and elevated transcriptional output of the pathway

“…It is reasonable to assume that at least a portion of the biologic effects of V600E BRAF are mediated by the expression of these genes. The importance of these genes for the biology of V600E BRAF tumors is supported by their overlap with genes identified as overexpressed in metastatic melanoma or mutant BRAF melanoma (27)(28)(29) (Table S3 and Fig. S6).…”

The involvement of the transcription factor Yin Yang 1 in cancer development and progression

“…Fifteen publicly available gene expression datasets were analyzed. 28,[35][36][37][38][39][40][41][42][43][44][45][46][47][48] Gene expression patterns of YY1 in nine different types of tumor and the relative normal counterpart were extracted from the normalized datasets (Table 2). This analysis reveals that YY1 transcript levels are significantly higher in cancer tissues than in the relative normal counterparts for each cancer type analyzed.…”

Myosin-1E interacts with FAK proline-rich region 1 to induce fibronectin-type matrix

“…MYO1E has previously been shown to localize to integrin adhesions (17) and to colocalize with paxillin in cancer cell invadosomes (16), where it promotes receptor-mediated endocytosis (18). In WM858 melanoma cells, a BRAF V600E cell line that expresses high amounts of FN and SPP1 (19), MYO1E organized into rosette-like structures surrounding a paxillin core (Fig. 2E).…”

“…5A). In these SPP1/ FN high-expressing cancer cells (19), the nuclear-to-cytoplasmic phospho-Y397 FAK ratio was high (Fig. 5B) compared with wildtype FAK-cherry reconstituted mouse embryonic fibroblasts (Fig.…”