Bae Seong-Yeon, Ling Hsiang-Hsi, Chen Yi, Chen Hong, Kumar Dhiraj, Zhang Jiankang, Viny Aaron D, DePinho Ronald A, Giancotti Filippo G
Cancer Metastasis Initiative, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York 10032, USA.
Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York 10032, USA.
bioRxiv. 2024 Nov 1:2023.11.18.566087. doi: 10.1101/2023.11.18.566087.
Long term survival of breast cancer patients is limited due to recurrence from metastatic dormant cancer cells. However, the mechanisms by which these dormant breast cancer cells survive and awaken remain poorly understood. Our unbiased genome-scale genetic screen in mice identified as a novel cancer-cell intrinsic gatekeeper in metastatic reactivation. haploinsufficiency is prevalent in metastatic breast cancer patients and correlates with poorer prognosis. Syngeneic xenograft models revealed that enforces breast cancer dormancy. Contrary to the canonical function of the Mediator complex in activating gene expression, maintains 3D chromatin compaction and enhancer landscape, by preventing enhancer priming or activation through the suppression of H3K4me1 deposition. haploinsufficiency disrupts enhancer poise and reprograms the enhancer dynamics to facilitate extracellular matrix (ECM) gene expression and integrin-mediated mechano-transduction, driving metastatic growth. Our findings establish as a key regulator of cellular dormancy and a potential biomarker for high-risk metastatic relapse.
由于转移性休眠癌细胞的复发，乳腺癌患者的长期生存率受到限制。然而，这些休眠乳腺癌细胞存活和苏醒的机制仍知之甚少。我们在小鼠中进行的无偏差全基因组遗传筛选确定了[具体基因名称]是转移重新激活过程中一种新的癌细胞内在守门人。[具体基因名称]单倍体不足在转移性乳腺癌患者中普遍存在，并且与较差的预后相关。同基因异种移植模型显示[具体基因名称]可维持乳腺癌休眠。与中介体复合物在激活基因表达中的经典功能相反，[具体基因名称]通过抑制H3K4me1沉积来防止增强子引发或激活，从而维持三维染色质压缩和增强子景观。[具体基因名称]单倍体不足会破坏增强子平衡，并重新编程增强子动态，以促进细胞外基质（ECM）基因表达和整合素介导的机械转导，驱动转移生长。我们的研究结果确立了[具体基因名称]作为细胞休眠的关键调节因子以及高风险转移复发的潜在生物标志物。
