@article{5717c641816f4df7b2722fcc2576b37b,
title = "The bone microenvironment invigorates metastatic seeds for further dissemination",
abstract = "Metastasis has been considered as the terminal step of tumor progression. However, recent genomic studies suggest that many metastases are initiated by further spread of other metastases. Nevertheless, the corresponding pre-clinical models are lacking, and underlying mechanisms are elusive. Using several approaches, including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. We uncovered that this metastasis-promoting effect is driven by epigenetic reprogramming that confers stem cell-like properties on cancer cells disseminated from bone lesions. Furthermore, we discovered that enhanced EZH2 activity mediates the increased stemness and metastasis capacity. The same findings also apply to single cell-derived populations, indicating mechanisms distinct from clonal selection. Taken together, our work revealed an unappreciated role of the bone microenvironment in metastasis evolution and elucidated an epigenomic reprogramming process driving terminal-stage, multi-organ metastases.",
keywords = "EZH2, bone metastasis, circulating tumor cells, disseminated tumor cells, epigenomic reprograming, evolving barcodes, organ tropism, plasticity, secondary metastasis, stemness",
author = "Weijie Zhang and Bado, {Igor L.} and Jingyuan Hu and Wan, {Ying Wooi} and Ling Wu and Hai Wang and Yang Gao and Jeong, {Hyun Hwan} and Zhan Xu and Xiaoxin Hao and Lege, {Bree M.} and Rami Al-Ouran and Lucian Li and Jiasong Li and Liqun Yu and Swarnima Singh and Lo, {Hin Ching} and Muchun Niu and Jun Liu and Weiyu Jiang and Yi Li and Wong, {Stephen T.C.} and Chonghui Cheng and Zhandong Liu and Zhang, {Xiang H.F.}",
note = "Funding Information: We would like to thank Zhang Laboratory members Dr. Lin Tian and Dr. Reza Kalhor for insightful discussion. Thanks also go to Epizyme (Cambridge, MA) for providing the EZH2 inhibitor EPZ-011989. We also acknowledge the Pathology Core of Lester and Sue Smith Breast Center, the Optical Imaging & Vital Microscopy (OiVM) core, the Genomic and RNA profiling core at Baylor College of Medicine, and Small Animal Imaging Facility (SAIF) core at Texas Children Hospital. X.H.-F.Z. is supported by US Department of Defense (DAMD W81XWH-16-1-0073 and DAMD W81XWH-20-1-0375), NCI (CA183878, CA227904, CA221946, and CA251950), the Breast Cancer Research Foundation, and McNair Foundation. S.S. is a recipient of CPRIT Training Grant (RP160283). S.T.C.W. and Jiasong Li are supported in part by NCI (U01CA252553), the John S. Dunn Research Foundation, and T.T. and W.F. Chao Center for BRAIN. C.C. is supported by the CPRIT Scholar Award (RR160009). This project was supported by the RNA In Situ Hybridization Core with a Shared Instrumentation grant from the NIH (1S10OD016167), the Cytometry and Cell Sorting Core with funding from the CPRIT Core Facility Support Award (CPRIT-RP180672), and the expert assistance of Dr. Cecilia Ljungberg and Joel M. Sederstrom at Baylor College of Medicine. Conceptualization and Methodology, W.Z. I.L.B. J.H. H.W. Z.L. and X.H.-F.Z.; Investigation, Formal Analysis and Validation, W.Z. I.L.B. J.H. Y.-W.W. L.W. H.W. Y.G. Z.X. X.H. B.M.L. R.A.-O. L.L. Jiasong Li, L.Y. H.C.L. M.N. Jun Liu, W.J. Z.L. and X.H.-F.Z.; Resources, Y.L. S.T.C.W. C.C. Z.L. and X.H.-F.Z.; Software, Data Curation, and Visualization, W.Z. I.L.B. J.H. Y.-W.W. H.-H.J. R.A.-O. L.L, S.S. Z.L. and X.H.-F.Z.; Writing – Original Draft, W.Z. I.L.B. J.H. and X.H.-F.Z.; Writing – Review & Editing, W.Z. H.C.L. S.T.C.W. and X.H.-F.Z.; Supervision, X.H.-F.Z.; Project Administration, W.Z. and X.H.-F.Z.; Funding Acquisition, S.T.C.W. C.C. and X.H.-F.Z. The authors declare no competing interests. Funding Information: We would like to thank Zhang Laboratory members Dr. Lin Tian and Dr. Reza Kalhor for insightful discussion. Thanks also go to Epizyme (Cambridge, MA) for providing the EZH2 inhibitor EPZ-011989. We also acknowledge the Pathology Core of Lester and Sue Smith Breast Center, the Optical Imaging & Vital Microscopy (OiVM) core, the Genomic and RNA profiling core at Baylor College of Medicine, and Small Animal Imaging Facility (SAIF) core at Texas Children Hospital. X.H.-F.Z. is supported by US Department of Defense ( DAMD W81XWH-16-1-0073 and DAMD W81XWH-20-1-0375 ), NCI ( CA183878 , CA227904 , CA221946 , and CA251950 ), the Breast Cancer Research Foundation , and McNair Foundation . S.S. is a recipient of CPRIT Training Grant ( RP160283 ). S.T.C.W. and Jiasong Li are supported in part by NCI ( U01CA252553 ), the John S. Dunn Research Foundation , and T.T. and W.F. Chao Center for BRAIN . C.C. is supported by the CPRIT Scholar Award ( RR160009 ). This project was supported by the RNA In Situ Hybridization Core with a Shared Instrumentation grant from the NIH ( 1S10OD016167 ), the Cytometry and Cell Sorting Core with funding from the CPRIT Core Facility Support Award ( CPRIT-RP180672 ), and the expert assistance of Dr. Cecilia Ljungberg and Joel M. Sederstrom at Baylor College of Medicine. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = apr,
day = "29",
doi = "10.1016/j.cell.2021.03.011",
language = "English (US)",
volume = "184",
pages = "2471--2486.e20",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "9",
}