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Войти в исследования Neuro-oncology · 2026
PTBP1 knockdown reprograms glioma stem cells into neuronal-like cells and suppresses tumorigenesis via the DUSP5-ERK1/2 signaling pathway.
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Li Cunyu, Chen Manyu, Guo Songyi, Ma Yuhao, Zhang Suli, Li Guanwei, Wu Jianqi, Liu Tianqi, Jin Yueyi, Liu Xing, Zhao Hu, Liu Hongmei, Wu Sijin, Jiang Hangjin, Cheng Wen, Wu Anhua, Hao Shuang
Аннотация
BACKGROUND: Glioblastoma (GBM), the most prevalent and aggressive primary brain tumor in adults, has a median survival of merely 14 months. Current therapeutic approaches, including maximal safe resection, radiotherapy, and temozolomide-based chemotherapy, have limited efficacy owing to resistance and the high rate of recurrence.
METHODS: We analyzed H&E-stained specimens from 65 patients with glioma using deep learning-based morphological classification and analyzed a mouse model through tissue clearing and 3D imaging. Integrated transcriptomic and single-cell RNA-seq analyses identified PTBP1 as a morphology regulator. We validated the function of PTBP1 through lentiviral knockdown in vitro and in orthotopic models and performed structure-based drug screening against PTBP1 with experimental validation.
RESULTS: We detected a clinically significant association between glioma cell morphology and patient survival times. Mechanistically, PTBP1, an RNA-binding protein abundantly expressed in glioma cells, regulated dual-specificity phosphatase 5 (DUSP5) expression post-transcriptionally and modulate ERK1/2 phosphorylation dynamics, thus reducing glioma stem cell proliferation and enhancing differentiation into neuronal-like cells to suppress tumor growth. Importantly, we developed a nanotherapeutic strategy using A2-PLGA/venetoclax; this strategy repurposes venetoclax, a known clinical drug for leukemia, as a PTBP1-targeting agent that effectively suppresses glioma progression in mouse models.
CONCLUSION: Our findings establish a novel PTBP1/DUSP5/ERK1/2 axis governing glioma stem cell proliferation and differentiation and identify the A2-PLGA/venetoclax nanoparticle as a mechanistically justified therapeutic candidate for glioblastoma.
METHODS: We analyzed H&E-stained specimens from 65 patients with glioma using deep learning-based morphological classification and analyzed a mouse model through tissue clearing and 3D imaging. Integrated transcriptomic and single-cell RNA-seq analyses identified PTBP1 as a morphology regulator. We validated the function of PTBP1 through lentiviral knockdown in vitro and in orthotopic models and performed structure-based drug screening against PTBP1 with experimental validation.
RESULTS: We detected a clinically significant association between glioma cell morphology and patient survival times. Mechanistically, PTBP1, an RNA-binding protein abundantly expressed in glioma cells, regulated dual-specificity phosphatase 5 (DUSP5) expression post-transcriptionally and modulate ERK1/2 phosphorylation dynamics, thus reducing glioma stem cell proliferation and enhancing differentiation into neuronal-like cells to suppress tumor growth. Importantly, we developed a nanotherapeutic strategy using A2-PLGA/venetoclax; this strategy repurposes venetoclax, a known clinical drug for leukemia, as a PTBP1-targeting agent that effectively suppresses glioma progression in mouse models.
CONCLUSION: Our findings establish a novel PTBP1/DUSP5/ERK1/2 axis governing glioma stem cell proliferation and differentiation and identify the A2-PLGA/venetoclax nanoparticle as a mechanistically justified therapeutic candidate for glioblastoma.