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Updated: May 13, 2026
Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Decreased PP2A expression and activity represent a therapeutic target for plexiform neurofibroma
Minghui Yue1,2, Yixiao Wang1, Jiabao Gu1
1Xuzhou Medical University, Xuzhou, China.
Abstract:
In neurofibromatosis type 1 (NF1), loss-of-function mutations in the NF1 gene increase activation of the RAS-MEK-ERK signaling cascade, driving tumorigenesis. MEK inhibitors (MEKi) inhibit tumor growth and significantly shrink nerve tumors (neurofibromas). However, MEKi treatment alone fails to eradicate tumor cells, and tumor regrowth occurs after drug withdrawal, highlighting the limitations of targeting the single MEK pathway. An alternative strategy is to promote dephosphorylation of hyperactive kinases that drive tumor growth by enhancing phosphatase activity. We identified deregulated expression of genes encoding subunits of the PP2A phosphatase in neurofibroma and neurofibroma Schwann cells. We confirmed significant reductions in both the expression and enzymatic activity of the PP2A A and C subunits. FTY720, a compound known to restore PP2A phosphatase activity, inhibited tumor sphere formation by mouse and human neurofibroma Schwann cell progenitor cells, suppressed the proliferation of both primary and immortalized neurofibroma-derived Schwann cells, and induced cell apoptosis in vitro. Furthermore, treatment with FTY720-alone or in combination with MEKi-significantly suppressed tumor number and reduced tumor burden in remaining tumors in a murine model of NF1, highlighting the promise of using FTY720 as a novel therapeutic strategy in NF1.
Insights
Neurofibromatosis type 1 (NF1) tumors are driven by the RAS-MEK-ERK pathway. Restoring PP2A phosphatase activity with FTY720 shows promise in treating NF1 tumors, alone or with MEK inhibitors.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Neurofibromatosis type 1 (NF1) is characterized by loss-of-function mutations in the NF1 gene, leading to increased RAS-MEK-ERK signaling and tumor formation.
- MEK inhibitors (MEKi) show efficacy in shrinking neurofibromas but do not eradicate tumor cells, leading to regrowth upon withdrawal.
- Enhancing phosphatase activity, specifically Protein Phosphatase 2A (PP2A), presents an alternative therapeutic strategy.
Purpose of the Study:
- To investigate the role of PP2A phosphatase in NF1 tumorigenesis.
- To evaluate FTY720, a PP2A activator, as a potential therapeutic agent for NF1.
Main Methods:
- Analysis of PP2A subunit expression and activity in NF1 neurofibroma and Schwann cells.
- In vitro assessment of FTY720's effects on neurofibroma Schwann cell progenitor proliferation, sphere formation, and apoptosis.
- In vivo evaluation of FTY720, alone and in combination with MEKi, in a murine model of NF1.
Main Results:
- Reduced expression and enzymatic activity of PP2A A and C subunits were observed in NF1 neurofibroma cells.
- FTY720 inhibited tumor sphere formation, suppressed proliferation, and induced apoptosis in NF1-derived Schwann cells.
- FTY720 treatment, alone or combined with MEKi, significantly reduced tumor burden in an NF1 mouse model.
Conclusions:
- Dysregulation of PP2A is implicated in NF1 tumorigenesis.
- FTY720 demonstrates therapeutic potential for NF1 by restoring PP2A activity and inhibiting tumor growth.
- FTY720 represents a promising novel therapeutic strategy for NF1, potentially in combination with existing treatments.
