Abstract
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.
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Acknowledgements
We thank Yusheng Wu and Prof. Xuerui Yang (Tsinghua University, China) for help with cell proliferation assay. We thank Qian Gao for help with HiSeq 1500 operation. We thank members of the Tsinghua University Animal Resources Center for their care of the mice. The results published here are in whole or part based upon data generated by The Cancer Genome Atlas managed by the NCI and NHGRI. Information about TCGA can be found at http://cancergenome.nih.gov. This work was supported by a grant from the National Natural Science Foundation of China (81673460, 31771461, 81972798) and funding from Tsinghua-Peking Joint Center for Life Sciences, Beijing Municipal Science & Technology Commission and Fok Ying-Tong Education Foundation. This study was also supported by Beijing Advanced Innovation Center for Structural Biology and Bio-Computing Platform of Tsinghua University Branch of China National Center for Protein Sciences (Beijing). I.G.B. is supported by the U.S. Department of Defense (W81XWH-14-1-0089 and W81XWH-12-1-0358), and the Ovarian Cancer Research Fund Alliance (Liz Tilberis Award) bequest from the Estate of Agatha Pepper Fort.
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D.W. and Z.J.L. conceived and supervised the project with assistance from I.G.B. S.S.T. performed the experiments with the help of M.Y., Q.Y.W., Y.M.Z., S.W.C., Y.C., Q.S.J., Q.Y.G., Z.C. and Y.J.C. Y.E.L. performed the computational analyses with the help from R.Q., Y.M.H., S.S.L., Q.K.L., Q.S.J. and Q.Y.G. D.W., Z.J.L. and S.S.T. wrote the manuscript with contributions from I.G.B., G.W., P.Y.W. and from all the rest of authors.
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Teng, S., Li, Y.E., Yang, M. et al. Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer. Cell Res 30, 34–49 (2020). https://doi.org/10.1038/s41422-019-0259-z
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DOI: https://doi.org/10.1038/s41422-019-0259-z
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