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Volume 30, No 1, Jan 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 1, January 2020: 34-49

ORIGINAL ARTICLES

Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer

Shuaishuai Teng1, Yang Eric Li 2,3, Ming Yang1, Rui Qi1, Yiming Huang2, Qianyu Wang1, Yanmei Zhang4, Shanwen Chen5, Shasha Li1,Kequan Lin2, Yang Cao1, Qunsheng Ji6, Qingyang Gu6, Yujing Cheng2, Zai Chang2, Wei Guo 7, Pengyuan Wang5, Ivan Garcia-Bassets8,Zhi John Lu2 and Dong Wang 1,9,10

1MOE Key Lab of Bioinformatics, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China; 2MOE Key Lab of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China; 3Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, CA 92093, USA; 4PKU-THU Center for Life Sciences, Tsinghua University, Beijing, China; 5Division of General Surgery, Peking University First Hospital, Peking University, Beijing, China; 6WuXi AppTec (Shanghai) Co., Ltd., Shanghai 200131, China; 7Zhejiang University-University of Edinburgh Institute, Haining, China; 8School of Medicine, University of California, San Diego, La Jolla, CA, USA; 9Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China and 10School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
 Correspondence: Zhi John Lu (zhilu@tsinghua.edu.cn) or Dong Wang (dwang@cdutcm.edu.cn)These authors contributed equally: Shuaishuai Teng, Yang Eric LiThese authors jointly supervised this work: Zhi John Lu, Dong Wang

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.


https://doi.org/10.1038/s41422-019-0259-z

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