YAP1 is a transcriptional coactivator and the principal effector of the Hippo signaling pathway, which is causally implicated in human cancer. Several YAP1 gene fusions have been identified in various human cancers and identifying the essential components of this family of gene fusions has significant therapeutic value. Here, we show that the YAP1 gene fusions YAP1-MAMLD1, YAP1-FAM118B, YAP1-TFE3, and YAP1-SS18 are oncogenic in mice. Using reporter assays, RNA-seq, ChIP-seq, and loss-of-function mutations, we can show that all of these YAP1 fusion proteins exert TEAD-dependent YAP activity, while some also exert activity of the C′-terminal fusion partner. The YAP activity of the different YAP1 fusions is resistant to negative Hippo pathway regulation due to constitutive nuclear localization and resistance to degradation of the YAP1 fusion proteins. Genetic disruption of the TEAD-binding domain of these oncogenic YAP1 fusions is sufficient to inhibit tumor formation in vivo, while pharmacological inhibition of the YAP1–TEAD interaction inhibits the growth of YAP1 fusion-expressing cell lines in vitro. These results highlight TEAD-dependent YAP activity found in these gene fusions as critical for oncogenesis and implicate these YAP functions as potential therapeutic targets in YAP1 fusion-positive tumors.

DDX3X is frequently mutated in the WNT and SHH subtypes of medulloblastomathe commonest malignant childhood brain tumor. But whether DDX3X functions as a medulloblastoma oncogene or tumor suppressor gene is not known. Here, we show that Ddx3x regulates hindbrain patterning and development by controlling Hox gene expression and cell stress signaling. In mice predisposed to Wnt or Shhmedulloblastoma, Ddx3x sensed oncogenic stress and suppressed tumor formation. WNT and SHHmedulloblastomas normally arise only in the lower and upper rhombic lips, respectively. Deletion of Ddx3x removed this lineage restriction, enabling both medulloblastoma subtypes to arise in either germinal zone.Thus, DDX3X is a medulloblastoma tumor suppressor that regulates hindbrain development and restricts the competence of cell lineages to form medulloblastoma subtypes.

ZFTA (C11orf95)—a gene of unknown function—partners with a variety of transcriptional coactivators in translocations that drive supratentorial ependymoma, a frequently lethal brain tumor. Understanding the function of ZFTA is key to developing therapies that inhibit these fusion proteins. Here, using a combination of transcriptomics, chromatin immunoprecipitation sequencing, and proteomics, we interrogated a series of deletion-mutant genes to identify a tripartite transformation mechanism of ZFTA-containing fusions, including: spontaneous nuclear translocation, extensive chromatin binding, and SWI/SNF, SAGA, and NuA4/Tip60 HAT chromatin modifier complex recruitment. Thereby, ZFTA tethers fusion proteins across the genome, modifying chromatin to an active state and enabling its partner transcriptional coactivators to promote promiscuous expression of a transforming transcriptome. Using mouse models, we validate further those elements of ZFTA-fusion proteins that are critical for transformation—including ZFTA zinc fingers and partner gene transactivation domains—thereby unmasking vulnerabilities for therapeutic targeting. Significance: Ependymomas are hard-to-treat brain tumors driven by translocations between ZFTA and a variety of transcriptional coactivators. We dissect the transforming mechanism of these fusion proteins and identify protein domains indispensable for tumorigenesis, thereby providing insights into the molecular basis of ependymoma tumorigenesis and vulnerabilities for therapeutic targeting. This article is highlighted in the In This Issue feature, p. 2113

Neurodegenerative disorders (NDs) are becoming one of the leading causes of disability and death across the globe due to lack of timely preventions and treatments. Concurrently, intensive research efforts are being carried out to understand the etiology of these age-dependent disorders. Extracellular vesicles (EVs)—biological nanoparticles released by cells—are gaining tremendous attention in understanding their role in pathogenesis and progression of NDs. EVs have been found to transmit pathogenic proteins of NDs between neurons. Moreover, the ability of EVs to exquisitely surmount natural biological barriers, including blood-brain barrier and in vivo safety has generated interest in exploring them as potential biomarkers and function as natural delivery vehicles of drugs to the central nervous system. However, limited knowledge of EV biogenesis, their heterogeneity and lack of adequate isolation and analysis tools have hampered their therapeutic potential. In this review, we cover the recent advances in understanding the role of EVs in neurodegeneration and address their role as biomarkers and delivery vehicles to the brain.

Ependymomas are the third most common paediatric brain tumour, incurable in up to 40% of cases. Until recently, ependymomas were regarded as a single disease group with all patients receiving combinations of maximal surgical resection and radiotherapy. Use of chemotherapy has been limited by the resistant nature of the tumour and poor access to tumours behind the blood brain barrier (BBB). It is now known that ependymoma comprises up to nine different molecular subgroups. One subgroup is characterized by a novel fusion protein, C11orf95-RELA, which acts as a potent driver of oncogenesis resulting in a poor prognosis. Here, we present the optimization of a novel drug delivery system that uses biodegradable hydrogels to deliver drugs with potent anti-ependymoma properties into post-resection cavity of supratentorial ependymoma. Our previous high-throughput in-vivo drug screens identified candidate ependymoma therapies with poor BBB penetrance properties. Using in-vitro delivery assays, we have confirmed and monitored the release of these compounds from the hydrogel. Additionally, we have implemented this delivery system in our preclinical mouse hospital in which mice receive standard-of-care surgery and radiotherapy. The efficacy of hydrogel-based delivery of these compounds is now being tested preclinically, in combination with radiotherapy. Treatment for ependymoma patients have not changed in the last 30 years and therefore an effective chemotherapy could add a great survival benefit to in the clinic.