G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA907236 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22478146.fastq.gz | Fastqsanger.gz | |||
| SRR22478147.fastq.gz | Fastqsanger.gz | |||
| SRR22478148.fastq.gz | Fastqsanger.gz | |||
| SRR22478149.fastq.gz | Fastqsanger.gz | |||
| SRR22478150.fastq.gz | Fastqsanger.gz |
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Project description:Neurofibromatosis Type II is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent growth of benign tumors from Schwann cells, the glia of the peripheral nervous system. Unfortunately, no pharmacological therapy is currently available for NFII. Here, we undertake a genome-wide CRISPR/cas9 screen to search for synthetic-lethal genes that, when inhibited, cause death of NF2 mutant cells but not NF2 wildtype cells. We thereby identify ACSL3 and G6PD as two synthetic-lethal partners for NF2. We find that NF2 mutant Schwann cells are vulnerable to G6PD inhibition because they have low levels of ME1. G6PD and ME1 redundantly generate cytosolic NADPH needed by cells to fight oxidative stress. Lack of either one of the two is compatible with cell viability, but down-regulation of both leads to Schwann cell death. Since genetic deficiency for G6PD is tolerated in the human population, this raises the possibility that G6PD could be a pharmacological target for NFII.
2024-04-24 | GSE219136 | GEO
Project description:Neurofibromatosis Type II is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent growth of benign tumors from Schwann cells, the glia of the peripheral nervous system. Unfortunately, no pharmacological therapy is currently available for NFII. Here, we undertake a genome-wide CRISPR/cas9 screen to search for synthetic-lethal genes that, when inhibited, cause death of NF2 mutant cells but not NF2 wildtype cells. We thereby identify ACSL3 and G6PD as two synthetic-lethal partners for NF2. We find that NF2 mutant Schwann cells are vulnerable to G6PD inhibition because they have low levels of ME1. G6PD and ME1 redundantly generate cytosolic NADPH needed by cells to fight oxidative stress. Lack of either one of the two is compatible with cell viability, but down-regulation of both leads to Schwann cell death. Since genetic deficiency for G6PD is tolerated in the human population, this raises the possibility that G6PD could be a pharmacological target for NFII.
2024-04-24 | GSE219135 | GEO
Project description:G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells
| PRJNA907229 | ENA
Project description:G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells
| PRJNA907235 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-04-24 | GSE219141 | GEO
Project description:Patients with neurofibromatosis type 2-related schwannomatosis (NF2-SWN) develop hallmark tumors on their vestibular nerves, leading to hearing loss and numerous associated morbidities. Currently, there are no targeted therapeutic options for treating these tumors. In prior work, our group had identified brigatinib as a potentially active drug in the treatment of murine models of NF2-SWN and meningioma, leading to a clinical trial in NF2-SWN patients testing brigatinib. Kinome profiling revealed that brigatinib resulted in the inhibition of focal adhesion kinase 1 (FAK1, encoded by the PTK2 gene). To test the contribution of FAK1, we generated a genetically engineered mouse model of NF2-SWN with Fak1/Ptk2 deletion in tumorigenic cells of origin. Genetic ablation of Fak1/Ptk2 preserved hearing in the mice and reduced tumorigenesis. Here we used an immortalized human Schwann cell line, 02.3 2lambda, Control and 3 NF2 KO clones, to perform kinome profiling.
2025-09-19 | PXD068581 | Pride
Project description:Patients with neurofibromatosis type 2-related schwannomatosis (NF2-SWN) develop hallmark tumors on their vestibular nerves, leading to hearing loss and numerous associated morbidities. Currently, there are no targeted therapeutic options for treating these tumors. In prior work, our group had identified brigatinib as a potentially active drug in the treatment of murine models of NF2-SWN and meningioma, leading to a clinical trial in NF2-SWN patients testing brigatinib. Kinome profiling revealed that brigatinib resulted in the inhibition of focal adhesion kinase 1 (FAK1, encoded by the PTK2 gene). To test the contribution of FAK1, we generated a genetically engineered mouse model of NF2-SWN with Fak1/Ptk2 deletion in tumorigenic cells of origin. Genetic ablation of Fak1/Ptk2 preserved hearing in the mice and reduced tumorigenesis. Here we used an immortalized Nf1 null Schwann cell line, MS03, to perform kinome profiling using the FAK inhibitors defactinib and VS-4718. Kinase enrichment proteomic analysis was performed using MS03 cells treated for 24 h with DMSO control, 1 micromolar defactinib, or 1 micromolar VS-4718 to evaluate the effects on the functional kinome.
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Project description:Loss of NF2 (merlin) has been suggested as a genetic cause of neurofibromatosis type 2 and malignant peripheral nerve sheath tumor (MPNST). Previously, we demonstrated that NF2 sustained TGF- receptor 2 (TR2) expression and reduction or loss of NF2 activated non-canonical TGF- signaling, which reduced RKIP expression via TR1 kinase activity. Here, we show that a selective RKIP inducer (novel chemical, Nf18001) inhibits tumor growth and promotes schwannoma cell differentiation into mature Schwann cells under NF2-deficient conditions. In addition, Nf18001 is not cytotoxic to cells expressing NF2 and is not disturb canonical TGF- signaling. Moreover, the novel chemical induces expression of SOX10, a marker of differentiated Schwann cells, and promotes nuclear export and degradation of SOX2, a stem cell factor. Treatment with Nf18001 inhibited tumor growth in an allograft model with mouse schwannoma cells. These results strongly suggest that selective RKIP inducers could be useful for the treatment of neurofibromatosis type 2 as well as NF2-deficient MPNST. To know the global effect of Nf18001, we performed the microarray with HEI-193.
2021-10-22 | GSE186107 | GEO
Project description:Neurofibromatosis type 2 is an inherited neoplastic disease consisting of schwannomas, meningiomas, and ependymomas that is caused by inactivation of the tumor suppressor gene NF2. The NF2 gene product, merlin, has no intrinsic catalytic activity; its tumor suppressor function is mediated through the proteins with which it interacts. However, there is no consensus about which merlin interactions are necessary for tumor suppression. We used proximity biotinylation followed by mass spectrometry and direct binding assays to characterize the proteins that associate with merlin and merlin mutants in immortalized Schwann cells. We identified 52 proteins that associate with merlin, including a previously unreported merlin binding protein, ASPP2. Our results identify merlin as a component of mechanosensing signal transduction pathways in cell junctions, in the context of a specific set of structures and molecules through which it acts, in a cell type relevant to schwannoma formation.
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