The Oncogenic EWS-FLI1 Protein Binds In Vivo GGAA Microsatellite Sequences with Potential Transcriptional Activation Function

The fusion between EWS and ETS family members is a key oncogenic event in Ewing tumors and important EWS-FLI1 target genes have been identified. However, until now, the search for EWS-FLI1 targets has been limited to promoter regions and no genome-wide comprehensive analysis of in vivo EWS-FLI1 binding sites has been undertaken. Using a ChIP-Seq approach to investigate EWS-FLI1-bound DNA sequences in two Ewing cell lines, we show that this chimeric transcription factor preferentially binds two types of sequences including consensus ETS motifs and microsatellite sequences. Most bound sites are found outside promoter regions. Microsatellites containing more than 9 GGAA repeats are very significantly enriched in EWS-FLI1 immunoprecipitates. Moreover, in reporter gene experiments, the transcription activation is highly dependent upon the number of repeats that are included in the construct. Importantly, in vivo EWS-FLI1-bound microsatellites are significantly associated with EWS-FLI1-driven gene activation. Put together, these results point out the likely contribution of microsatellite elements to long-distance transcription regulation and to oncogenesis

Mesenchymal Stem Cells During Tumor Formation and Dissemination

The tumor microenvironment (TME) is composed by malignant and non-malignant cells, all embedded in a dense extracellular matrix (ECM) rich with unstable vessels. Targeting TME components, especially those associated with the vasculature such as endothelial cells (ECs) and pericytes, has shown clinical benefits. The identity correlation between pericytes and mesenchymal stem cells (MSC) has broadened the functional roles of these adult stem cells, now tightly involved in cancer biology. This review summarizes this involvement, focusing on their participation in: 1) skeletal primary malignancies; 2) formation of distant primary tumors; 3) intravasation of cancer cells at the primary tumors; and 4) extravasation of cancer cells at the target organ. Given their tropism to sites of injury and inflammation, bone marrow (BM)-derived MSC (BM-MSC) follow tumor-derived signals and participate in the formation of distant primary tumors, by repopulating their perivascular habitat and contributing to tumor growth. Thus, targeting primary tumor’s pericytes severely reduces growth, yet dissemination of constitutive cancer cells increases. The impact of pericyte-deficient coverage on the target organ is rather opposite, generating a selective reduction of cancer cell invasion in some organs. These roles seem to be founded on the distinct molecular communication and physical interactions between MSC as pericytes and the cancer cells