Abstract
The Ewing Sarcoma Family Tumors (ESFT) consist of the classical pathologic entities of Ewing Sarcoma and peripheral Primitive Neuroectodermal Tumor. Occurring largely in the childhood through young adult years, these tumors have an unsurpassed propensity for metastasis and have no defined cell of origin. The biology of these aggressive malignancies centers around EWS/FLI1 and related EWS/ETS chimeric transcription factors, which are largely limited to this tumor class. Much progress has been made in the identification of a network of loci whose expression is modulated by EWS/FLI1 and its congeners. To date, little progress has been made in reconstructing the sequence of direct and indirect events that produce this network of modulated loci. The recent identification of GLI1 as an upregulated target of EWS/ETS transcription factors suggests a target which may be a more central mediator in the ESFT signaling network. In this paper, we further define the relationship of EWS/FLI1 expression and GLI1 upregulation in ESFT. This relationship is supported with data from primary tumor specimens. It is consistently observed across multiple ESFT cell lines and with multiple means of EWS/FLI1 inhibition. GLI1 inhibition affects tumor cell line phenotype whether shRNA or endogenous or pharmacologic inhibitors are employed. As is seen in model transformation systems, GLI1 upregulation by EWS/FLI1 appears to be independent of Hedgehog stimulation. Consistent with a more central role in ESFT pathogenesis, several known EWS/FLI1 targets appear to be targeted through GLI1. These findings further establish a central role for GLI1 in the pathogenesis of Ewing Tumors.
Highlights
Much of the unique biology of the Ewing Sarcoma Family Tumors (ESFT) stems from the unique effects of EWS/FLI1
Primary tumors demonstrate significant GLI1 expression Our earlier findings focused on EWS/FLI1 activation of GLI1 in an NIH3T3 model transformation system[4] with added data from ESFT cell lines
HH-GLI pathway activity has been found to be diminished in in vitro cultured medulloblastoma lines[12], so the cell lines we evaluated may not reflect the condition in primary ESFT
Summary
Much of the unique biology of the Ewing Sarcoma Family Tumors (ESFT) stems from the unique effects of EWS/FLI1. Given the nature of these chimeric proteins, considerable work has gone into the identification of the transcriptional targets of EWS/FLI1[2,3]. Despite this effort, no identified target has been clinically demonstrated to be of prognostic or therapeutic significance. No identified target has been clinically demonstrated to be of prognostic or therapeutic significance Together, this diverse group of targets constitute a signaling network. This diverse group of targets constitute a signaling network Elements of this transcriptional network have been identified[3] but the relationship between these elements has not been well studied. Establishing the existence and nature of such relationships will be critical to prioritizing which transcriptional targets are most likely to have maximal impact as targets for translational therapeutics
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