Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer
Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer
复制标题
组织特异性转录重编程促进结直肠癌肝转移
DOI：
10.1038/s41422-019-0259-z
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发表时间：
2020-01-01
期刊：
影响因子：
44.1
通讯作者：
Wang, Dong
中科院分区：
文献类型：
--
作者：
Teng, Shuaishuai;Li, Yang Eric;Wang, Dong
转移是指在距离原发肿瘤较远的地方发生的继发性恶性生长，是90%的癌症患者死亡的原因，但人们对转移的癌细胞如何适应和定居新的组织环境知之甚少。在这里，我们利用临床样本、患者来源的异种移植(PDX)样本、PDX细胞和原代/转移细胞系，发现肝转移性结直肠癌(CRC)细胞失去了其结肠特异的基因转录程序，但获得了肝脏特异的基因转录程序。我们证明了这种转录重新编程是由典型增强子和超级增强子的重塑的表观遗传格局驱动的。进一步，我们发现肝脏特异的转录因子FOXA2和HNF1A可以与所获得的增强子结合，激活肝脏特异的基因转录，从而驱动结直肠癌的肝转移。重要的是，相似的转录重编程可以在多种癌症类型中观察到。我们的数据表明，重新编程的组织特异性转录促进转移，应该作为治疗的靶点。
Metastasis, the development of secondary malignant growths at a distance from a primary tumor, is the cause of death for 90% of cancer patients, but little is known about how metastatic cancer cells adapt to and colonize new tissue environments. Here, using clinical samples, patient-derived xenograft (PDX) samples, PDX cells, and primary/metastatic cell lines, we discovered that liver metastatic colorectal cancer (CRC) cells lose their colon-specific gene transcription program yet gain a liver-specific gene transcription program. We showed that this transcription reprogramming is driven by a reshaped epigenetic landscape of both typical enhancers and super-enhancers. Further, we identified that the liver-specific transcription factors FOXA2 and HNF1A can bind to the gained enhancers and activate the liver-specific gene transcription, thereby driving CRC liver metastasis. Importantly, similar transcription reprogramming can be observed in multiple cancer types. Our data suggest that reprogrammed tissue-specific transcription promotes metastasis and should be targeted therapeutically.