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PP2A Regulates Senescence and Immunogenicity in Medulloblastoma

ABSTRACT: Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Current treatments carry significant morbidity, and prognosis remains poor in subgroups with TP53 mutations or relapse, underscoring the need for new therapeutic strategies. Senescence is a tumor-suppressive program disrupted in MB. We hypothesized that restoring senescence through p53-independent mechanisms could be therapeutic. Here, we identify Protein Phosphatase 2A (PP2A) as a key regulator of senescence in MB. Genetic ablation of the PP2A catalytic subunit (PP2Ac) or knockdown of the regulatory subunit PP2A-B56α induces robust senescence in TP53-mutant MB models. Senescent PP2Ac-deficient cells show increased MHC-I expression and enhanced immunogenicity. In a syngeneic orthotopic model, PP2Ac loss prolongs survival in an immune- and CD8-dependent manner, indicating enhanced immune-mediated tumor clearance. Analysis of MB patient datasets links senescence signatures with improved survival, and integrative single-cell analysis reveals reduced PP2A activity in immunogenic senescent clusters. Although the PP2A inhibitor LB-100 is under clinical investigation, it fails to cross the blood-brain barrier. To overcome this, we developed a lipid nanoparticle (LNP) formulation delivering siRNA against PP2Ac. LNP-siPP2Ac efficiently silences PP2Ac in vitro and, when locally delivered in vivo, extends survival and increases tumor MHC-I expression. These findings establish PP2A as a central modulator of senescence and immunogenicity in MB and support a therapeutic strategy that induces tumor cell senescence and enhances anti-tumor immunity for treatment of MB.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE302307 | GEO | 2026/04/11

REPOSITORIES: GEO

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Project description:Protein phosphatase 2A (PP2A) is one of the most common serine/threonine phosphatases in mammalian cells and primarily functions to regulate cell signaling, glycolipid metabolism, and apoptosis. Its PP2A catalytic subunit (PP2Ac) plays an important role in its function. Nonetheless, at present, there are only a few reports on the regulatory role of PP2Ac in pancreatic β-cells under lipotoxicity. Mouse pancreatic insulinoma (MIN6) cells were transfected by lentiviruses to generate PP2Ac knockdown cells and incubated with palmitate (PA) to establish the lipotoxicity model. Serine/Threonine Phosphatase Assay System kit, Cell Counting Kit-8 (CCK-8), flow cytometry, enzyme-linked immunosorbent assay (ELISA), Western Blotting (WB) and other techniques were used to measure PP2A activity, cell viability, apoptosis, oxidative stress, and insulin secretion. An animal model of lipotoxicity with knockdown of PP2Ac was established by a high-fat diet (HFD) after using adeno-associated viruses (AAV) to interfere with PP2Ac expression in mouse pancreatic tissues. Serine/Threonine Phosphatase Assay System kit, ELISA, pancreatic tissue immunofluorescence and other techniques were used to measure PP2A activity in pancreatic tissue, serum insulin level and the proliferation of mouse pancreatic β-cells. We found that PP2Ac knockdown inhibited lipotoxicity-induced PP2A hyperactivation, increased the resistance of pancreatic β-cells to lipotoxicity, decreased PA-induced apoptosis in MIN6 cells, protected the function of both the endoplasmic reticulum (ER) and mitochondria, and improved insulin secretion. By mRNA sequencing and Western blotting analysis, we hypothesized that the protective effects of PP2Ac knockdown in MIN6 cells may be mediated by the MAPK pathway. Moreover, the results obtained from animal experiments suggest that the specific knockdown of pancreatic PP2Ac could effectively attenuate HFD-induced insulin resistance and reduce the compensatory proliferation of pancreatic β-cells in mice. The present study revealed the effects and mechanisms of interfering with PP2Ac gene expression on pancreatic β-cells in vivo and in vitro, which might provide insights for the treatment of type 2 diabetes in the clinic.

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PP2A Regulates Senescence and Immunogenicity in Medulloblastoma

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