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Transcriptome profiling of NF1 MPNST line ST88-14 (8814) after ZNF423 shRNA knockdown

ABSTRACT: Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas and the leading cause of mortality in neurofibromatosis type 1 (NF1), with limited systemic therapies. Malignant progression can reactivate developmental precursor programs that are largely absent from normal nerve and benign tumors, creating tumor-selective vulnerabilities. Zinc finger protein 423 (ZNF423; also known as OAZ/ROAZ) is a developmentally regulated transcription factor that delays olfactory precursor differentiation and has been implicated in Bcell malignancy. Here, we asked whether ZNF423 is reactivated and functionally required in NF1-associated MPNST. In genetically defined models, Nf1 loss reduced Zfp423 in a benign tumor cell-of-origin context, whereas combined Nf1 and Cdkn2a loss induced marked Zfp423 upregulation during transformation. ZNF423 depletion impaired DNA synthesis and proliferation, induced DNA damage signaling, and activated the integrated stress response (ISR), increasing sensitivity to cytotoxic agents. Sustained shRNA-mediated ZNF423 suppression compromised tumor initiation in vivo, with eventual outgrowth associated with restoration of ZNF423 expression. ZNF423 is developmentally restricted in the peripheral nerve lineage yet elevated in MPNST, and single-cell analyses of patient nerve sheath tumors localized expression to malignant cells rather than SOX10-positive benign tumor cells. These data identify a potential ZNF423 dependency in a subset of NF1-MPNST and nominate downstream stress and genome maintenance pathways as therapeutic vulnerabilities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE320231 | GEO | 2026/09/11

REPOSITORIES: GEO

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Project description:Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials. 83 microarrays: Mouse control (15), Mouse neurofibroma (15), Mouse MPNST (18); Human nerve (3), Human neurofibroma (26), Human MPNST (6) We used the same human tumor samples as in series GSE14038 (dNF, pNF and MPNST). However, instead of referencing gene expression changes to the normal human Schwann cell samples (NHSC) as we did in series GSE14038, we generated three (new) normal nerve samples (samples jan-N1-3) and referenced gene expression changes to those samples. Moreover, the analysis of series GSE14038 evaluated changes in expression between NHSC, benign tumor subtypes (dNF and pNF), and malignant tumors (MPNST), while our present submission evaluated changes between normal nerve, benign tumors (combined dNF and pNF),and malignant tumors (MPNST). The Series supplementary 'merged_data.txt' file contains the data for 9,891 transcripts that were statistically different in at least one of the two species and present in both mouse and human data sets.

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Transcriptome profiling of NF1 MPNST line ST88-14 (8814) after ZNF423 shRNA knockdown

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