Highlights of This Issue

Abstract

The EWS/FLI (EF) fusion protein is well known as an aberrant transcription factor that drives oncogenesis in Ewing sarcoma by inducing widespread transcriptional reprogramming. In this issue, Tanner and colleagues explore the previously unstudied role of EF in driving metabolic misregulation. Silencing of EF resulted in significant changes in the global metabolic profile and glucose utilization. Additionally, it was demonstrated that EF is required for high expression of de novo serine synthesis and 1-carbon metabolism pathways, which correlated with worse patient survival. These findings expand the understanding of Ewing sarcoma biology and offer potential new avenues of therapeutic development.Incurable castration-resistant prostate cancer (CRPC) is often accompanied by unrestrained androgen receptor (AR) signaling driven by (currently undruggable) constitutively active, C-terminally truncated AR variants (e.g., AR-V7); which retain the potent transactivating N-terminal domain of AR. Transcriptional activities of AR and variants are enhanced by select coactivators (e.g., Vav3) with elevated expression in CRPC. Magani and colleagues demonstrate that Vav3 (via its DH domain) interacts with the N-termini of AR and AR-V7. Vav3 DH domain overexpression disrupts coactivator interactions with and transcriptional activities of AR-V7 and AR, decreasing CRPC aggressiveness. This study identifies AR N-terminal coactivator interactions as exploitable vulnerabilities in CRPC.Spontaneous nuclear envelope (NE) rupture has been observed in several cancer cell lines but does not occur in untransformed human cells. NE rupture can lead to mixing of nuclear and cytoplasmic factors and may compromise genome integrity. Yang and colleagues have identified the tumor suppressor proteins Rb and p53 as suppressors of NE rupture. Depletion of either Rb or p53 increased the frequency of NE rupture in primary cells. This finding reveals novel protective functions of Rb and p53 and provides a mechanistic explanation for the occurrence of NE rupture in cancer cells.Glioblastoma (GBM) is an invasive and malignant brain cancer. Heparan sulfate proteoglycans (HSPG), present on cell surfaces and in the extracellular matrix (ECM), regulate cell signaling and cell-microenvironment interactions. Heparan sulfate (HS) expression and enzymes that modulate their function are altered in GBM, but the actual HS content and structure are unknown. Using liquid chromatography-mass spectrometry (LC/MS), Tran and colleagues define the patterns of HS structure and their modification in patient-derived tumorspheres. Using this approach, a novel role is uncovered for the HS-modifying enzyme heparanase in GBM invasion. These results suggest that HS-interacting factors are potential therapeutic targets in GBM.