Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyperproliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide profiling reveals that TAZ/YAP-TEAD1 directly activates oncogenic programs, including platelet-derived growth factor receptor (PDGFR) signaling. Co-targeting TAZ/YAP and PDGFR pathways inhibits tumor growth. Thus, our findings establish a previously unrecognized convergence between Lats1/2-TAZ/YAP signaling and MPNST pathogenesis, revealing potential therapeutic targets in these untreatable tumors.

中文翻译：

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Lats1 / 2-TAZ / YAP信号传导对许旺细胞的编程可驱动恶性周围神经鞘瘤的发生。

恶性周围神经鞘瘤（MPNSTs）是高度侵袭性的雪旺细胞（SC）谱系来源的肉瘤。驱动SC到MPNST转化的分子事件尚不完全清楚。在这里，我们显示人类MPNSTs表现出高的HIPPO-TAZ / YAP表达，并且由Lats1 / 2丢失引起的SC中的TAZ / YAP过度活跃会强烈诱导出具有高渗透率的高级神经相关肿瘤。Lats1 / 2缺乏症可将SC重新编程为癌性祖细胞样表型，并促进过度增殖。相反，破坏TAZ / YAP活性可减轻Lats1 / 2缺陷小鼠的肿瘤负担，并抑制人MPNST细胞的增殖。此外，全基因组分析显示TAZ / YAP-TEAD1直接激活致癌程序，包括血小板衍生的生长因子受体（PDGFR）信号传导。共同靶向TAZ / YAP和PDGFR途径抑制肿瘤生长。因此，我们的发现在Lats1 / 2-TAZ / YAP信号传导和MPNST发病机理之间建立了以前无法识别的融合，揭示了这些不可治愈的肿瘤中潜在的治疗靶标。