Inactivation of p21-Activated Kinase 2 (Pak2) Inhibits the Development of Nf2-Deficient Tumors by Restricting Downstream Hedgehog and Wnt Signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA792572 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17335157_1.fastq.gz | Fastqsanger.gz | |||
| SRR17335157_2.fastq.gz | Fastqsanger.gz | |||
| SRR17335158_1.fastq.gz | Fastqsanger.gz | |||
| SRR17335158_2.fastq.gz | Fastqsanger.gz | |||
| SRR17335159_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 16 |
Similar Datasets
Project description:Since loss of the NF2 tumor suppressor gene results in p21-activated kinase (Pak) activation, PAK inhibitors hold promise for the treatment of NF2-deficient tumors. To test this possibility, we asked if loss of Pak2, a highly expressed group I PAK member, affects the development of malignant mesothelioma in Nf2;Cdkn2a-deficient (NC) mice and the growth properties of NC mesothelioma cells in culture. In vivo, deletion of Pak2 resulted in a markedly decreased incidence and delayed onset of both pleural and peritoneal malignant mesotheliomas in NC mice. In vitro, Pak2 deletion decreased malignant mesothelioma cell viability, migration, clonogenicity, and spheroid formation. RNA-seq analysis demonstrated downregulated expression of Hedgehog and Wnt pathway genes in NC;Pak2-/- mesothelioma cells versus NC;Pak2+/+ mesothelioma cells. Targeting of the Hedgehog signaling component Gli1 or its target gene Myc inhibited cell viability and spheroid formation in NC;P+/+ mesothelioma cells. Kinome profiling uncovered kinase changes indicative of EMT in NC;Pak2-/- mesothelioma cells, suggesting that Pak2-deficient malignant mesotheliomas can adapt by reprogramming their kinome in the absence of Pak activity. The identification of such compensatory pathways offers opportunities for rational combination therapies to circumvent resistance to anti-PAK drugs.
2023-03-10 | PXD030571 | Pride
Project description:RNAseq analysis revealled that the expression of Hedgehog and Wnt pathway members were altered by Pak2 gene knockout during mesotheliomagenesis.
2022-12-27 | GSE192660 | GEO
Project description:We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics. Analysis of meningioma gene expression data for each mutation subtype. Includes gene expression data from 75 unique meningiomas and 39 replicates.
2014-05-29 | E-GEOD-58037 | biostudies-arrayexpress
Project description:Cardiac differentiation involves a stepwise clearance of repressors and fate-restricting regulators through the modulation of BMP/Wnt-signaling pathways. However, the mechanisms and how regulatory roadblocks are removed with specific developmental signaling pathways remain unclear. Here, we performed a genome-wide CRISPR screen to uncover essential regulators of cardiomyocyte specification in human embryonic stem cells (hESCs) and identify NF2, a Moesin-Ezrin-Radixin Like (MERLIN) Tumor Suppressor, as an upstream driver of cardiomyocyte specification. Transcriptional regulation and trajectory inference from NF2-null cells reveal the loss of cardiomyocyte identity and the acquisition of non-mesodermal identity. Sustained elevation of early mesoderm lineage repressor SOX2 and upregulation of late anti-cardiac regulators CDX2, MSX1 in NF2 knockout cells reflect a necessary role for NF2 in removing regulatory roadblocks. Since YAP is a known repressor of mesendoderm genes, we found that NF2 and AMOT cooperatively bind to YAP during mesendoderm formation, thereby preventing YAP activation independent on canonical MST-LATS1 kinase activity. Mechanistically, cardiomyocyte lineage identity was rescued by wild-type and NF2 Serine-518 phospho-mutants, but not NF2 FERM-domain blue-box mutants, showing that the critical FERM domain-dependent formation of the AMOT-NF2-YAP scaffold complex at the adherens junction is required for cardiomyocyte lineage differentiation. These results provide mechanistic insight into the essential role of NF2 for cardiomyocyte lineage specification by sequestering the repressive effect of YAP and relieving regulatory roadblocks en route to cardiomyocytes.
2024-04-30 | GSE244362 | GEO
Project description:We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.
2014-05-29 | GSE58037 | GEO
Project description:Neurofibromatosis type 2 (NF2) syndrome is a very rare human genetic disease and until now, it’s proper treatment has not been suggested. In our recent study, it has been reported that the loss of NF2 activates MAPK signaling through reduction of RKIP in a mesothelioma model. Here, we show that loss of NF2 induces reduction of the TGF-β receptor 2 (TβR2) expression and an overwhelming expression of TGF-β receptor 1 is activated by physical stimuli such as pressure or heavy materials. Activated TR1 induced the phosphorylation and degradation of RKIP. RKIP reduction consequently results in MAPK activation as well as Snail-mediated p53 suppression and occurrence of EMT in NF2-deficient cells by physical stimuli. Thus, TβR1 kinase inhibitors restore cell differentiation and induce growth suppression in NF2 deficient Schwannoma cell line and MEF. Moreover, TEW7197, a specific TβR1 kinase inhibitor, reduces tumor formation in the NF2-model mouse (Postn-Cre;NF2f/f). Gene expression profiling reveals that TEW7197-treatment induces the expression of lipid metabolism-related gene set such as NF2-restored cells in HEI-193 (NF2-deficient Schwannoma). Our results indicate that reduction or deletion of TβR2 or NF2 induces the TβR1-mediated oncogenic pathway, and therefore inhibition of the unbalanced TGF-β signaling is a putative strategy for NF2-related cancers (NF2 syndrome and mesothelioma) and TβR2 mutated advanced cancers. To know the global effect of TEW7197, we performed the microarray with HEI-193.
2018-06-06 | GSE115359 | GEO
Project description:Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset is of higher grade, recurs even after multiple surgeries, and frequently fatal. Around half of meningiomas harbor inactivating mutations in NF2. While low-grade NF2 mutant meningiomas harbor few additional mutations in addition to NF2 inactivation, high-grade NF2 mutant tumors frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as an oncogene in NF2 mutant meningiomas. Here, we show that high-grade NF2 mutant meningiomas downregulate YAP1 signaling, in part through upregulating the expression of the YAP1 competitor VGLL4 and the YAP1 upstream regulators FAT3/4. Overexpression of VGLL4 resulted in the downregulation of YAP activity and the growth inhibition of low-grade NF2 mutant meningioma cells. Our results have important implications for the efficacy of therapies targeting oncogenic YAP1 in high-grade NF2 mutant meningiomas.
2024-08-26 | GSE263122 | GEO
Project description:Macrophages play critical roles in immune function and are implicated as etiological agents in disease states such as cardiovascular disease and cancer. However, there is limited understanding of macrophage fitness molecular regulators, including survival, proliferation, and adhesion. This work identifies positive and negative regulators of macrophage fitness by harnessing the power of CRISPR/Cas9 whole genome screening technology. Here, we identified loss-of-function gene disruptions that caused mutant bone marrow-derived macrophages (BMDM) to decrease in culture abundance as supporters of macrophage fitness. Similarly, we identified genes that limit or suppress macrophage fitness by identifying those gene disruptions that caused BMDM to increase in abundance in cell culture. To do this, we analyzed the difference in frequency of sgRNA between the purified plasmid library used for lentiviral transfection versus the amplified sgRNA inserts from the DNA of BMDM following a 14-day post-viral transduction culture. With this approach, we identified gene disruptions to canonical essential genes, including previously described macrophage-specific essential genes such as Csf1r, as well as novel genes required for macrophage growth and survival. In addition, we also identified gene disruptions that increased macrophage abundance in culture, including canonical tumor suppressors such as p53 (Trp53) and cell cycle regulators (Cdkn1a/2a). Interestingly, targeting p21-activated kinase-2 (Pak2) led to those mutants becoming more productive, suggesting a novel role for Pak2 in suppressing macrophage fitness. Using targeted knockouts of PAK2, we show that PAK2 protein depletion affects NF2/Merlin-mediated downregulation of cyclin-d1. Further, this work indicates that PAK2 suppresses macropinocytic uptake in macrophages by modulating actin dynamics impacting pro-mitogenic signaling pathways downstream of macropinocytosis. Overall, this work shows how multiple pathways impact macrophage fitness and highlights the central role of PAK2 in macrophage fitness and macropinocytosis.
2024-05-01 | GSE251887 | GEO
Project description:To transcriptomic differences among control, Nf2 KO, Rasa1 KO, and double KO S1 tumorspheres We then performed gene expression profiling analysis using data obtained from RNA-seq of control, Nf2 KO, Rasa1 KO, and double KO S1 tumorspheres.
2023-09-27 | GSE239457 | GEO
Project description:Primary liver cancer is the third leading cause of cancer related death worldwide. An increasing body of evidence suggests that the Hippo tumor suppressor pathway plays a critical role in restricting cell proliferation and determining cell fate during physiological and pathological processes in the liver. Merlin (Moesin-Ezrin-Radixin-likeprotein), encoded by the NF2 (neurofibromatosis type 2) gene is an upstream regulator of the Hippo signaling pathway. Targeting of Merlin to the plasma membrane seems to be critical for fulfilling its major tumor-suppressive functions; this is facilitated by interactions with membrane-associated proteins, including CD44 (clusterofdifferentiation44). Indeed, mutations within the CD44-binding domain of Merlin were reported in many human cancers. In this study, we evaluated the relative contribution of CD44- and Merlin-dependent processes to the development and progression of liver tumors. To this end, mice with liver-specific deletion of the Nf2 gene were crossed with Cd44-deleted mice, and subjected to extensive histological, biochemical and molecular analyses. In addition, cells were isolated from mutant livers and subjected to in vitro assays. Deletion of Nf2 in the liver led to substantial liver enlargement and generation of hepatocellular carcinomas (HCCs), intrahepatic cholangiocarcinomas (iCCAs) as well as mixed hepatocellular cholangiocarcinomas. Deletion of Cd44 had no influence on liver size or primary liver tumor development but it significantly inhibited metastasis formation in Nf2-mutant mice. CD44 upregulates expression of integrin β2 and promotes transendothelial migration of liver cancer cells which may facilitate metastatic spreading. Altogether, our results suggest that CD44 may be a promising target for interfering with metastatic spreading of liver cancer.
2023-05-17 | GSE228630 | GEO