The bone microenvironment invigorates metastatic seeds for further dissemination

Weijie Zhang, Igor L. Bado, Jingyuan Hu, Ying Wooi Wan, Ling Wu, Hai Wang, Yang Gao, Hyun Hwan Jeong, Zhan Xu, Xiaoxin Hao, Bree M. Lege, Rami Al-Ouran, Lucian Li, Jiasong Li, Liqun Yu, Swarnima Singh, Hin Ching Lo, Muchun Niu, Jun Liu, Weiyu JiangYi Li, Stephen T.C. Wong, Chonghui Cheng, Zhandong Liu, Xiang H.F. Zhang

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2471-2486.e20
JournalCell
Volume184
Issue number9
DOIs
StatePublished - Apr 29 2021

Keywords

  • EZH2
  • bone metastasis
  • circulating tumor cells
  • disseminated tumor cells
  • epigenomic reprograming
  • evolving barcodes
  • organ tropism
  • plasticity
  • secondary metastasis
  • stemness

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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