Ewing Sarcoma, an enigmatic malignancy of likely progenitor cell origin, driven by transcription factor oncogenic fusions

Abstract

Since its first description by James Ewing in 1921, Ewing Sarcoma has been a cryptic malignancy. A poorly differentiated tumor of uncertain histogenesis and aggressive biologic behavior, it is the second most common malignancy of bone and soft tissue affecting adolescents and young adults. Some two decades ago, the understanding of Ewing Sarcoma biology took a leap forward with the identification of recurrent EWS/Ets fusions, which drive onco-genesis in this disease. A further leap forward occurred over the last half decade with the application of gene silencing, global expression profiling and primary cell culture technologies to the study of this disease. Resulting work has revealed EWS/Ets fusions to be surprisingly versatile regulators of gene expression, and has narrowed the search for the elusive cell of origin. Improved understanding of EWS/Ets biology and relevant oncogenic pathways has in turn led to the development of targeted therapies, including, recently, small molecules targeting key complexes involving the oncogenic fusion itself. In many respects still remaining an enigma, Ewing Sarcoma is an important model for cancers originating in progenitor-type cells or manifesting progenitor-type cell features, and cancers containing recurrent oncogenic fusions, the latter a surprisingly expanding number.

Keywords: Ewing Sarcoma; fusion oncogene; progenitor cell; transcription factor.

Figure 1

EWS/Ets gene regulatory pathways. EWS/Fli1 and other EWS/Ets fusions both activate and repress gene expression. EWS/Fli1 activates some target genes directly, through Ets DNA-binding sites (EBS) or through GGAA mi-crosatellites [(GGAA)_n]. Some target genes are coreguiated (activated or repressed) with the transcriptionai coregula-tor NR0B1, itself an EWS/Fli1-induced gene. EWS/Fli1 is also able to repress some target genes directly, through Ets DNA-binding sites (EBS). Additional mechanisms of target gene repression are induction of the transcriptionai repres-sor Nkx2.2, and induction of the histone methyltransferase EZH2. EWS/Ets fusions may also regulate target gene expression through non-transcriptional mechanisms, including RNA processing.

Figure 2

Growth factor pathways regulated by EWS/Ets oncogenic fusions with demonstrated functions in Ewing Sarcoma oncogenesis. Pro-oncogenic (green) and tumor suppressive (red) targets of EWS/Ets fusions in growth factor pathways. Pro-oncogenic targets include PDGF-C, the mediator of Hedgehog-Smoothened signaling Gli1, IGF-1 and DKK2, a regulator of Wnt signaling. mTOR, downstream of IGF-1 signaling, may positively regulate EWS/Ets fusion levels. EWS/Fli1 antagonizes nuclear (3-catenin transcriptional activity, possibly by sequestering Lef. EWS/Ets-regulated tumor suppressive targets with demonstrated function in Ewing Sarcoma include TGFβRII and DKK1. The expression of DKK1 and DKK2 appears to be mutually antagonistic.