Purpose: Ewing sarcoma is the second most common bone sarcoma in children, with 1 case per 1.5 million in the United States. Although the survival rate of patients diagnosed with localized disease is approximately 70%, this decreases to approximately 30% for patients with metastatic disease and only approximately 10% for treatment-refractory disease, which have not changed for decades. Therefore, new therapeutic strategies are urgently needed for metastatic and refractory Ewing sarcoma. Experimental Design: This study analyzed 19 unique Ewing sarcoma patient- or cell line–derived xenografts (from 14 primary and 5 metastatic specimens) using proteomics to identify surface proteins for potential immunotherapeutic targeting. Plasma membranes were enriched using density gradient ultracentrifugation and compared with a reference standard of 12 immortalized non–Ewing sarcoma cell lines prepared in a similar manner. In parallel, global proteome analysis was carried out on each model to complement the surfaceome data. All models were analyzed by Tandem Mass Tags–based mass spectrometry to quantify identified proteins. Results: The surfaceome and global proteome analyses identified 1,131 and 1,030 annotated surface proteins, respectively. Among surface proteins identified, both approaches identified known Ewing sarcoma–associated proteins, including IL1RAP, CD99, STEAP1, and ADGRG2, and many new cell surface targets, including ENPP1 and CDH11. Robust staining of ENPP1 was demonstrated in Ewing sarcoma tumors compared with other childhood sarcomas and normal tissues. Conclusions: Our comprehensive proteomic characterization of the Ewing sarcoma surfaceome provides a rich resource of surface-expressed proteins in Ewing sarcoma. This dataset provides the preclinical justification for exploration of targets such as ENPP1 for potential immunotherapeutic application in Ewing sarcoma. See related commentary by Bailey, p. 934

The presence of fluid in the brain ventricles has been known since the ancient Egyptians. However, the first mention of CSF circulation did not occur until 1532, when the Italian anatomist Niccolò Massa first described the movement of a “watery excess” through brain foramina ([Herbowski, 2013][

Brain tumors represent some of the most aggressive malignancies

In spite of recent advances in tumour molecular subtyping, pediatric brain tumours (PBTs) remain the leading cause of cancer-related deaths in children. While some PBTs are treatable with favourable outcomes, recurrent and metastatic disease for certain types of PBTs remains challenging and is often fatal. Tumour immunotherapy has emerged as a hopeful avenue for the treatment of childhood tumours, and recent immunotherapy efforts have been directed towards PBTs. This strategy has the potential to combat otherwise incurable PBTs, while minimizing off-target effects and long-term sequelae. As the infiltration and activation states of immune cells, including tumour-infiltrating lymphocytes and tumour-associated macrophages, are key to shaping responses towards immunotherapy, this review explores the immune landscape of the developing brain and discusses the tumour immune microenvironments of common PBTs, with hopes of conferring insights that may inform future treatment design.

RNA modifications are emerging as critical regulators in cancer biology, thanks to their ability to influence gene expression and the predominant protein isoforms expressed during cell proliferation, migration, and other pro-oncogenic properties. The reversibility and dynamic nature of post-transcriptional RNA modifications allow cells to quickly adapt to microenvironmental changes. Recent literature has revealed that the deregulation of RNA modifications can promote a plethora of developmental diseases, including tumorigenesis. In this review, we will focus on four key post-transcriptional RNA modifications which have been identified as contributors to the pathogenesis of brain tumors: m⁶A, alternative polyadenylation, alternative splicing and adenosine to inosine modifications. In addition to the role of RNA modifications in brain tumor progression, we will also discuss potential opportunities to target these processes to improve the dismal prognosis for brain tumors.