癌症研究
生物
肺泡软组织肉瘤
TFE3型
转录因子
表观遗传学
细胞生长
血管生成
细胞周期蛋白D1
癌症
增强子
细胞生物学
细胞周期
肉瘤
医学
病理
遗传学
基因
作者
Ewa Sicinska,Vijaya S.R. Kola,Joseph A. Kerfoot,Madeleine L. Taddei,Alyaa Al‐Ibraheemi,Yi-Hsuan Hsieh,Alanna J. Church,Esther Landesman‐Bollag,Yosef Landesman,Matthew L. Hemming
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-04-24
被引量:1
标识
DOI:10.1158/0008-5472.can-23-2115
摘要
Abstract 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.
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