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1.
Sci Adv ; 8(40): eabo6789, 2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36206341

RESUMO

Temporally regulated alternative splicing choices are vital for proper development, yet the wrong splice choice may be detrimental. Here, we highlight a previously unidentified role for the neurotrophin receptor splice variant TrkB.T1 in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in humans and mice. TrkB.T1 is the predominant NTRK2 isoform across embryonic organogenesis, and forced overexpression of this embryonic pattern causes multiple solid and nonsolid tumors in mice in the context of tumor suppressor loss. TrkB.T1 also emerges as the predominant NTRK isoform expressed in a wide range of adult and pediatric tumors, including those harboring tropomyosin receptor kinase fusions. Affinity purification-mass spectrometry proteomic analysis reveals distinct interactors with known developmental and oncogenic signaling pathways such as Wnt, transforming growth factor-ß, Sonic Hedgehog, and Ras. From alterations in splicing factors to changes in gene expression, the discovery of isoform specific oncogenes with embryonic ancestry has the potential to shape the way we think about developmental systems and oncology.

2.
Genes Dev ; 2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36008139

RESUMO

YAP1 is a transcriptional coactivator regulated by the Hippo signaling pathway, including NF2. Meningiomas are the most common primary brain tumors; a large percentage exhibit heterozygous loss of chromosome 22 (harboring the NF2 gene) and functional inactivation of the remaining NF2 copy, implicating oncogenic YAP activity in these tumors. Recently, fusions between YAP1 and MAML2 have been identified in a subset of pediatric NF2 wild-type meningiomas. Here, we show that human YAP1-MAML2-positive meningiomas resemble NF2 mutant meningiomas by global and YAP-related gene expression signatures. We then show that expression of YAP1-MAML2 in mice induces tumors that resemble human YAP1 fusion-positive and NF2 mutant meningiomas by gene expression. We demonstrate that YAP1-MAML2 primarily functions by exerting TEAD-dependent YAP activity that is resistant to Hippo signaling. Treatment with YAP-TEAD inhibitors is sufficient to inhibit the viability of YAP1-MAML2-driven mouse tumors ex vivo. Finally, we show that expression of constitutively active YAP1 (S127/397A-YAP1) is sufficient to induce similar tumors, suggesting that the YAP component of the gene fusion is the critical driver of these tumors. In summary, our results implicate YAP1-MAML2 as a causal oncogenic driver and highlight TEAD-dependent YAP activity as an oncogenic driver in YAP1-MAML2 fusion meningioma as well as NF2 mutant meningioma in general.

3.
J Neurosurg ; 132(6): 1706-1714, 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31125970

RESUMO

OBJECTIVE: 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence is an effective surgical adjunct for the intraoperative identification of tumor tissue during resection of high-grade gliomas. The use of 5-ALA-induced PpIX fluorescence in glioblastoma (GBM) has been shown to double the extent of gross-total resection and 6-month progression-free survival. The heterogeneity of 5-ALA-induced PpIX fluorescence observed during surgery presents a technical and diagnostic challenge when utilizing this tool intraoperatively. While some regions show bright fluorescence after 5-ALA administration, other regions do not, despite that both regions of the tumor may be histopathologically indistinguishable. The authors examined the biological basis of this heterogeneity using computational methods. METHODS: The authors collected both fluorescent and nonfluorescent GBM specimens from a total of 14 patients undergoing surgery and examined their gene expression profiles. RESULTS: In this study, the authors found that the gene expression patterns characterizing fluorescent and nonfluorescent GBM surgical specimens were profoundly different and were associated with distinct cellular functions and different biological pathways. Nonfluorescent tumor tissue tended to resemble the neural subtype of GBM; meanwhile, fluorescent tumor tissue did not exhibit a prominent pattern corresponding to known subtypes of GBM. Consistent with this observation, neural GBM samples from The Cancer Genome Atlas database exhibited a significantly lower fluorescence score than nonneural GBM samples as determined by a fluorescence gene signature developed by the authors. CONCLUSIONS: These results provide a greater understanding regarding the biological basis of differential fluorescence observed intraoperatively and can provide a basis to identify novel strategies to maximize the effectiveness of fluorescence agents.

5.
Cancer Res ; 78(21): 6031-6039, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30333116

RESUMO

Cellular secretion is an important mediator of cancer progression. Secreted molecules in glioma are key components of complex autocrine and paracrine pathways that mediate multiple oncogenic pathologies. In this review, we describe tumor cell secretion in high-grade glioma and highlight potential novel therapeutic opportunities. Cancer Res; 78(21); 6031-9. ©2018 AACR.


Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Vesículas Extracelulares/metabolismo , Glioma/metabolismo , Glioma/terapia , Humanos , Camundongos , Transplante de Neoplasias , Oncogenes , Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Resposta a Proteínas não Dobradas
6.
Mol Cancer Ther ; 16(4): 705-716, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28138037

RESUMO

Despite abundant evidence implicating receptor tyrosine kinases (RTK), including the platelet-derived growth factor receptor (PDGFR), in the pathogenesis of glioblastoma (GBM), the clinical use of RTK inhibitors in this disease has been greatly compromised by the rapid emergence of therapeutic resistance. To study the resistance of proneural gliomas that are driven by a PDGFR-regulated pathway to targeted tyrosine kinase inhibitors, we utilized a mouse model of proneural glioma in which mice develop tumors that become resistant to PDGFR inhibition. We found that tumors resistant to PDGFR inhibition required the expression and activation of the insulin receptor (IR)/insulin growth-like factor receptor (IGF1R) for tumor cell proliferation and survival. Cotargeting IR/IGF1R and PDGFR decreased the emergence of resistant clones in vitro Our findings characterize a novel model of glioma recurrence that implicates the IR/IGF1R signaling axis in mediating the development of resistance to PDGFR inhibition and provide evidence that IR/IGF1R signaling is important in the recurrence of the proneural subtype of glioma in which PDGF/PDGFR is most commonly expressed at a high level. Mol Cancer Ther; 16(4); 705-16. ©2017 AACR.


Assuntos
Neoplasias Encefálicas/genética , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/genética , Receptor IGF Tipo 1/genética , Receptor de Insulina/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Esferoides Celulares/patologia , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Cromonas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Mesilato de Imatinib/farmacologia , Imidazóis/farmacologia , Insulina/metabolismo , Camundongos , Morfolinas/farmacologia , Transplante de Neoplasias , Pirazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Esferoides Celulares/transplante , Células Tumorais Cultivadas , Tirfostinas/farmacologia
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