Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma

Laraba, Liyam; Guibert, Julio Grimm de; Hewitt, Amy; Jaques, Maisie R; Tang, Tracy; Post, Leonard; Ercolano, Emanuela; Rai, Ganesha; Yang, Shyh Ming; Jagger, Daniel J.; Woznica, Waldemar; Edwards, Peter G.; Shivane, Aditya G.; Hanemann, C. Oliver; Parkinson, David B.

doi:10.1093/brain/awac342

Cited by 21 publications

(13 citation statements)

References 78 publications

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“…Such arrangement can lead to changes in the nuclear to cytoplasmic connections and facilitate the aberrant transport of nuclear effector/oncogenes in the NF2 mutant background. One such example is the protein YAP, which is known to aid NF2- mediated tumorigenesis (Guerrant et al, 2016; Laraba et al, 2022; Oh et al, 2015; Szulzewsky et al, 2022). While several studies have explored the functional role of YAP in combination with NF2 in tumorigenesis, the mechanobiological aspect of their interaction is yet to be decoded.…”

Section: Discussionmentioning

confidence: 99%

Generation of a zebrafish neurofibromatosis model via inducible knockout ofnf2

Desingu Rajan,

Huang,

Stundl

et al. 2024

Preprint

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Neurofibromatosis Type 2 (NF-2) is a dominantly inherited genetic disorder that results from mutations in the tumor suppressor gene, neurofibromin 2 (NF2) gene. Here, we report the generation of a conditional zebrafish model of neurofibromatosis established by an inducible genetic knockout of nf2a/b, the zebrafish homolog of human NF2. Analysis of nf2a and nf2b expression reveals ubiquitous expression of nf2b in the early embryo, with overlapping expression in the neural crest and its derivatives and in the cranial mesenchyme. In contrast, nf2a displays lower expression levels. Induction of nf2a/b knockout at early stages increases the proliferation of larval Schwann cells and meningeal fibroblasts. Subsequently, in adult zebrafish, nf2a/b knockout triggers the development of a spectrum of tumors, including vestibular schwannomas, spinal schwannomas, meningiomas, and retinal hamartomas, mirroring the tumor manifestations observed in patients with NF-2. Collectively, these findings highlight the generation of a novel zebrafish model that mimics the complexities of the human NF-2 disorder. Consequently, this model holds significant potential for facilitating therapeutic screening and elucidating key driver genes implicated in NF-2 onset.

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Section: Discussionmentioning

confidence: 99%

Generation of a zebrafish neurofibromatosis model via inducible knockout ofnf2

Desingu Rajan,

Huang,

Stundl

et al. 2024

Preprint

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“…Loss of NF2 results in deregulation and activation of oncogenic YAP activity and increased levels of YAP activity have been observed in NF2 mutant over NF2 wild type meningiomas 11,12 . Oncogenic YAP activity has also been implicated in the pathobiology of other tumors harboring inactivating NF2 mutations [44][45][46][47] . We have previously shown that the expression of an oncogenic point mutant YAP construct is able to induce the formation of meningioma-like tumors in mice 13 .…”

Section: Discussionmentioning

confidence: 99%

Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4

Parrish,

Arora,

Thirimanne

et al. 2024

Preprint

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Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset of meningiomas is of higher grade, shows aggressive growth behavior and recurs even after multiple surgeries. Around half of all meningiomas harbor inactivating mutations in NF2. While benign low-grade NF2 mutant meningiomas exhibit few genetic events in addition to NF2 inactivation, aggressive high-grade NF2 mutant meningiomas frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as the pivotal oncogenic driver in benign NF2 mutant meningiomas. Using bulk and single-cell RNA-Seq data from a large cohort of human meningiomas, we show that aggressive NF2 mutant meningiomas harbor decreased levels YAP1 activity compared to their benign counterparts. Decreased expression levels of YAP target genes are significantly associated with an increased risk of recurrence. We then identify the increased expression of the YAP1 competitor VGLL4 as well as the YAP1 upstream regulators FAT3/4 as a potential mechanism for the downregulation of YAP activity in aggressive NF2 mutant meningiomas. High expression of these genes is significantly associated with an increased risk of recurrence. In vitro, overexpression of VGLL4 resulted in the downregulation of YAP activity in benign NF2 mutant meningioma cells, confirming the direct link between VGLL4 expression and decreased levels of YAP activity observed in aggressive NF2 mutant meningiomas. Our results shed new insight on the biology of benign and aggressive NF2 mutant meningiomas and may have important implications for the efficacy of therapies targeting oncogenic YAP1 activity in NF2 mutant meningiomas.

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“…Recent advancement has been made in the search for novel therapeutic approaches to treat meningiomas. Studies have demonstrated that blocking the interaction between YAP1 and TEAD or targeting TEAD auto-palmitoylation can effectively inhibit tumor formation and suppress tumor growth in the YAP1 fusion/ NF2 mutant meningioma and schwannoma [ 15 , 20 , 21 ]. However, the number of reported YAP1 fusion meningioma cases remains limited.…”

Section: Discussionmentioning

confidence: 99%

Atypical Intraparenchymal Meningioma with YAP1-MAML2 Fusion in a Young Adult Male: A Case Report and Mini Literature Review

Nobee

Seth

et al. 2023

IJMS

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Oncogenic Yes-associated protein (YAP) 1 fusions have been recently identified in several cases of meningioma mostly involving pediatric patients. The meningiomas harboring YAP1-MAML2, which is the most frequent fusion subtype, exhibit activated YAP1 signaling and share similarities with NF2 (neurofibromatosis type 2 gene) mutant meningiomas. We reported a rare case of atypical intraparenchymal meningioma with YAP1-MAML2 fusion in a 20-year-old male. The patient presented with an episode of seizure without a medical history. MRI revealed a lesion in the right temporal lobe without extra-axial involvement. The radiological and morphological findings, however, were indistinctive from other intracranial diseases, e.g., vascular malformation and glioma. Immunohistochemical results confirmed the presence of abundant meningothelial cells in the tumor and indicated brain invasion, supporting the diagnosis of atypical intraparenchymal meningioma. Targeted RNA fusion analysis further identified a YAP1-MAML2 rearrangement in the tumor. Non-dural-based intraparenchymal meningiomas are uncommon, and the careful selection of specific tumor markers is crucial for an accurate diagnosis. Additionally, the detection of the fusion gene provides valuable insights into the oncogenic mechanism of meningioma.

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Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma

Cited by 21 publications

References 78 publications

Generation of a zebrafish neurofibromatosis model via inducible knockout ofnf2

Generation of a zebrafish neurofibromatosis model via inducible knockout ofnf2

Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4

Atypical Intraparenchymal Meningioma with YAP1-MAML2 Fusion in a Young Adult Male: A Case Report and Mini Literature Review

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