Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer.,Cell Research

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Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer.
Cell Research ( IF 28.1 ) Pub Date : 2019-12-06 , DOI: 10.1038/s41422-019-0259-z
Shuaishuai Teng ₁ , Yang Eric Li _{2,

3} , Ming Yang ₁ , Rui Qi ₁ , Yiming Huang ₂ , Qianyu Wang ₁ , Yanmei Zhang ₄ , Shanwen Chen ₅ , Shasha Li ₁ , Kequan Lin ₂ , Yang Cao ₁ , Qunsheng Ji ₆ , Qingyang Gu ₆ , Yujing Cheng ₂ , Zai Chang ₂ , Wei Guo ₇ , Pengyuan Wang ₅ , Ivan Garcia-Bassets ₈ , Zhi John Lu ₂ , Dong Wang _{1,

9,

10}

Affiliation

MOE Key Lab of Bioinformatics, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China.
MOE Key Lab of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.
Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
PKU-THU Center for Life Sciences, Tsinghua University, Beijing, China.
Division of General Surgery, Peking University First Hospital, Peking University, Beijing, China.
WuXi AppTec (Shanghai) Co., Ltd., Shanghai, 200131, China.
Zhejiang University-University of Edinburgh Institute, Haining, China.
School of Medicine, University of California, San Diego, La Jolla, CA, USA.
Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.

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.

中文翻译：

组织特异性转录重编程促进结直肠癌肝转移。

转移，即远离原发肿瘤的继发性恶性生长，是 90% 癌症患者的死亡原因，但人们对转移性癌细胞如何适应和定植新的组织环境知之甚少。在这里，使用临床样本、患者来源的异种移植 (PDX) 样本、PDX 细胞和原代/转移细胞系，我们发现肝转移性结直肠癌 (CRC) 细胞失去了其结肠特异性基因转录程序，但获得了肝脏特异性基因转录程序。基因转录程序。我们表明，这种转录重编程是由典型增强子和超级增强子的重塑表观遗传景观驱动的。此外，我们还发现肝脏特异性转录因子FOXA2和HNF1A可以与获得的增强子结合并激活肝脏特异性基因转录，从而驱动CRC肝转移。重要的是，在多种癌症类型中都可以观察到类似的转录重编程。我们的数据表明，重编程的组织特异性转录可促进转移，应作为治疗目标。

更新日期：2019-12-06

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