Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignancy driven by the ASPSCR1::TFE3 fusion. A better understanding of the mechanisms by which this oncogenic transcriptional regulator drives cancer growth is needed to help identify potential therapeutic targets. Here, we characterized the transcriptional and chromatin landscapes of ASPS tumors and preclinical models, identifying the essential role of ASPSCR1::TFE3 in tumor cell viability by regulating core transcriptional programs involved in cell proliferation, angiogenesis, and mitochondrial biology. ASPSCR1::TFE3 directly interacted with key epigenetic regulators at enhancers and promoters to support ASPS-associated transcription. Among the effector programs driven by ASPSCR1::TFE3, cell proliferation was driven by high levels of cyclin D1 expression. Disruption of cyclin D1/CDK4 signaling led to loss of ASPS proliferative capacity, and combined inhibition of CDK4/6 and angiogenesis halted tumor growth in xenografts. These results define the ASPS oncogenic program, reveal mechanisms by which ASPSCR1::TFE3 controls tumor biology, and identify a strategy for therapeutically targeting tumor cell-intrinsic vulnerabilities.

中文翻译：

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ASPSCR1::TFE3 通过诱导靶向转录程序驱动肺泡软组织肉瘤

腺泡软组织肉瘤 (ASPS) 是一种罕见的间叶恶性肿瘤，由 ASPSCR1::TFE3 融合驱动。需要更好地了解这种致癌转录调节因子驱动癌症生长的机制，以帮助确定潜在的治疗靶点。在这里，我们描述了 ASPS 肿瘤和临床前模型的转录和染色质景观，通过调节涉及细胞增殖、血管生成和线粒体生物学的核心转录程序，确定了 ASPSCR1::TFE3 在肿瘤细胞活力中的重要作用。 ASPSCR1::TFE3 直接与增强子和启动子处的关键表观遗传调节因子相互作用，以支持 ASPS 相关转录。在 ASPSCR1::TFE3 驱动的效应程序中，细胞增殖是由高水平的细胞周期蛋白 D1 表达驱动的。细胞周期蛋白 D1/CDK4 信号传导的破坏会导致 ASPS 增殖能力的丧失，而 CDK4/6 和血管生成的联合抑制会阻止异种移植物中的肿瘤生长。这些结果定义了 ASPS 致癌程序，揭示了 ASPSCR1::TFE3 控制肿瘤生物学的机制，并确定了针对肿瘤细胞内在脆弱性的治疗策略。