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Contribution of mTOR and PTEN to Radioresistance in Sporadic and NF2-Associated Vestibular Schwannomas: A Microarray and Pathway Analysis.

ABSTRACT: The use of radiation treatment has increased for both sporadic and neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS). However, there are a subset of radioresistant tumors and systemic treatments that are seldom used in these patients. We investigated molecular alterations after radiation in three NF2-associated and five sporadically operated recurrent VS after primary irradiation. We compared these findings with 49 non-irradiated (36 sporadic and 13 NF2-associated) VS through gene-expression profiling and pathway analysis. Furthermore, we stained the key molecules of the distinct pathway by immunohistochemistry. A total of 195 differentially expressed genes in sporadic and NF2-related comparisons showed significant differences based on the criteria of p value < 0.05 and a two-fold change. These genes were involved in pathways that are known to be altered upon irradiation (e.g., mammalian target of rapamycin (mTOR), phosphatase and tensin homolog (PTEN) and vascular endothelial growth factor (VEGF) signaling). We observed a combined downregulation of PTEN signaling and an upregulation of mTOR signaling in progressive NF2-associated VS after irradiation. Immunostainings with mTOR and PTEN antibodies confirmed the respective molecular alterations. Taken together, mTOR inhibition might be a promising therapeutic strategy in NF2-associated VS progress after irradiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141801 | GEO | 2020/01/24

REPOSITORIES: GEO

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Project description:Object: The main limitation of treatment strategies for vestibular schwannomas (VSs) is loss of function of vestibulocochlear and facial nerves, which has driven investigations into new pharmaceutical therapies. The most common genetic alteration in human VSs is loss ofthe NF2 gene which encodes the protein merlin. It is well established that merlin achieves tumor suppressive functions through regulation of the Hippo pathway. The aim of this study was to analyze dysregulation of the Hippo pathway in sporadic VSs and to identify whether Hippo signaling could be potential targetable pathway for treatment of VS. Methods: In this study, we performed gene expression profiling of ten human sporadic VSs and four normal control vestibular nerves to identify aberrant expression of the Hippo pathway in VSs. Molecular subtypes in VSs was evaluated using unsupervised hierarchical clustering analysis. Western blot analysis and immunohistochemical staining were used to examine the expression of Hippo pathway core components in twenty human sporadic VSs. NF2 gene sequencing and mutation analysis were performed in all VS samples. Ki67 marker was used to investigate proliferation of tumor cells. Verteporfin was used to determine whether the inhibitor of YAP-TEAD reduced proliferation of human primary VS cells with NF2 mutations and RT4-D6P2T cell line. Results: We found fifty-one differentially expressed genes between VSs and controls. Unsupervised analysis of transcriptional profiles identified the two distinct molecular variants, which was significantly associated with NF2 mutation status. The protein level of MST2, LAST2,phospho-LAST1, and phospho-YAP were significantly decreased in VSs compared with normal tissues. Nuclear YAP staining was positively correlated with Ki-67 indexin VS samples. Finally, verteporfin reduced viability of human primary VS cells and in a dose-dependent manner by decreasing YAP expression. Conclusions: Our findings implicate that deregulation of the Hippo pathway as a molecular mechanism of pathogenesis in human sporadic VSs, and suggest inhibition of this pathway as a potential treatment strategy.

Project description:Children are considered more sensitive to radiation-induced cancer than adults, yet any differences in genomic alterations associated with age at exposure and their underlying mechanisms remain unclear. We analyzed the mutation of key tumor suppressor genes in T-cell lymphomas arising after weekly irradiation of female B6C3F1 mice with 1.2 Gy X-rays for 4 consecutive weeks starting during infancy (1 week old), adolescence (4 weeks old) or as young adults (8 weeks old). T-cell lymphoma incidence did not show any statistical differences among three irradiated groups; however, the frequency of loss of heterozygosity on chromosomes 11 and 19 showed opposing correlations with age at exposure. Ikaros on chromosome 11 was mutated frequently in the young adultâ??irradiation group (63%; 5/8), frequently incurring multiple independent hits (including deletions and mutations) or suffering a single hit predicted to result in a dominant negative protein (such as those lacking exon 4, an isoform we have designated Ik11, which lacks two of the four zincâ??finger domains important for DNA binding). Pten on chromosome 19 was mutated more frequently in tumors from infant- (67%; 10/15) compared with young adult-irradiated mice (13%; 1/8, P = 0.041). Despite the presence of homozygous Pten mutations, DNA copy number was unchanged in the infant-irradiation group, suggesting duplication of the mutated allele by chromosome mis-segregation or mitotic recombination. Taken together, our findings demonstrate that while deletions on chromosome 11 affecting the Ikaros locus are a prominent feature of young adult irradiation-induced T-cell lymphoma, tumors arising after infant irradiation suffer a second hit in the Pten gene by chromosome mis-segregation or recombination. This is the first report showing age-at-exposure associated radiation-induced genomic alterations in two key tumor suppressor genes linked to T-cell lymphomagenesis. These data are important for considering the risks associated with childhood exposure to radiation. 38 T-cell lymphomas arising after weekly irradiation of female B6C3F1 mice with 1.2 Gy X-rays for 4 consecutive weeks starting at different ages (Infant: 1 week old (15 tumors), Adolescent: 4 weeks old (13 tumors), Young adult: 8 weeks old (10 tumors)) were analyzed.

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Contribution of mTOR and PTEN to Radioresistance in Sporadic and NF2-Associated Vestibular Schwannomas: A Microarray and Pathway Analysis.

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