Mechanisms Identified as Contributors to Metastasis in Ewing’s Sarcoma

Researchers from Colorado published a study identifying potential mechanisms involved in the higher rate of metastasis in Ewing’s sarcoma.

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As the second most common bone and soft tissue cancer in children and young adults, Ewing’s sarcoma is an aggressive pediatric disease notorious for its high rate of metastasis and poor patient outcomes.

Researchers from the University of Colorado in Aurora, Colorado, USA, published a paper in Oncotarget—a world-class and free-to-read scientific journal—detailing their study providing the first evidence of a cancer-promoting role for the PHF2 gene, among KDM5A and other genes responsible for promoting metastasis in Ewing’s sarcoma.

EWS/Fli1 in “Low State”

In preceding studies, researchers identified the role of the fused protein (previously two independent genes) EWS/Fli1 as a driver in 90% of Ewing’s sarcoma gene repression, cancer cell proliferation, survival, oncogenic transformation, and tumor growth. However, the researchers in this study acknowledged that less is known about the particular mechanisms fueling the high rate of metastasis in Ewing’s sarcoma.

Previous studies also show that Ewing’s sarcoma cells in the EWS/Fli1 low state demonstrate an increased propensity for metastasis. Since Ewing’s sarcoma is a disease shaped by epigenetic dysregulation, or gene expression influenced by non-genetic factors, the researchers studied epigenetic mechanisms in hopes of better understanding their contributions to the metastasis and progression of Ewing’s sarcoma.

KDM5A and PHF2 Genes in EWS/Fli1

The team investigated the functional roles of KDM5A and PHF2 genes, based on data showing a correlation between higher expression levels and more aggressive Ewing’s sarcoma. Their study began by stably depleting the expression of both genes in Ewing’s sarcoma cell lines using lentiviral delivery of shRNAs. The depletion of KDM5A and PHF2 both resulted in the inhibition of tumor formation—indicating that both factors exert growth-promoting effects in Ewing’s sarcoma.

Via gene set enrichment analysis, the researchers uncovered another striking discovery: the depletion of KDM5A and PHF2 resulted in the down-regulation of the EWS/Fli1 repressed gene signature. 

“Having shown that KDM5A and PHF2 promote metastatic properties in Ewing sarcoma, and exert effects on metastasis in opposition to those of EWS/Fli1, we wondered whether inhibition of KDM5A or/and PHF2 could impair the biological properties of more metastatically potent EWS/Fli1low cells.” 

The researchers examined the above quandary by stably depleting KDM5A and PHF2 expression in EWS/Fli1low cells. Consistent with findings previously published, EWS/Fli1low cells grew at a slower rate. Therefore, researchers asserted that KDM5A and PHF2 maintain their growth-promoting properties in EWS/Fli1low cells, while PHF2 contributes to the increased invasive potential of this cell population.

“Our studies thus provide the first evidence for a disease-promotional role for PHF2 in cancer, and highlight the context-dependent action of epigenetic regulators in biology.”

Prognostic Marker: L1CAM

In further research, the team identified L1CAM as variably expressed in Ewing’s sarcoma. L1CAM is overexpressed in a variety of cancers, and has been shown to be capable of exerting both tumor and metastasis-promoting effects.

“Here, we identify L1CAM as variably expressed in Ewing sarcoma, strongly induced upon EWS/Fli1 down-regulation, and strongly associated in expression with adverse clinical outcome. We further show that L1CAM promotes Ewing sarcoma cell migratory and invasive properties when expressed at high levels.”

Their studies suggest that L1CAM may be another gene/protein that could provide an alternative method of inhibiting the aggressive biology of the EWS/Fli1low cell population.

Conclusion

This study identifies prognostic markers and shows that the epigenetic regulators KDM5A and PHF2 promote growth and metastatic properties in Ewing’s sarcoma, while activating the expression of many pro-metastatic genes that were repressed by EWS/Fli1.

Further exploration of these mechanisms may help to shed more light on Ewing’s sarcoma and the molecular basis behind its metastatic propensity. The researchers also say that it may present new approaches for metastasis inhibition, including a solution for reversing the high metastatic potency of cells with low EWS/Fli1 expression.

Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read – without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues and other researchers, far and wide.

Click here to read the full scientific paper, published in Oncotarget.

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