Dataset Information

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.

SUBMITTER: Zhang W

PROVIDER: S-EPMC8087656 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The bone microenvironment invigorates metastatic seeds for further dissemination.

Zhang Weijie W Bado Igor L IL Hu Jingyuan J Wan Ying-Wooi YW Wu Ling L Wang Hai H Gao Yang Y Jeong Hyun-Hwan HH Xu Zhan Z Hao Xiaoxin X Lege Bree M BM Al-Ouran Rami R Li Lucian L Li Jiasong J Yu Liqun L Singh Swarnima S Lo Hin Ching HC Niu Muchun M Liu Jun J Jiang Weiyu W Li Yi Y Wong Stephen T C STC Cheng Chonghui C Liu Zhandong Z Zhang Xiang H-F XH

Cell 20210419 9

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 ...[more]

PMID: 33878291

Similar Datasets

Project description:BackgroundOsteosarcoma is the most prevalent cancer-related bone disease diagnosed in the pediatric age group. The rapid development of metastatic lesions and resistance to chemotherapy remain major mechanisms responsible for the failure of treatments and poor outcome. We established that the expression level of Cysteine-rich protein 61 (CYR61/CCN1) correlates to tumor neo-vascularization and dissemination in preclinical and clinical osteosarcoma samples. The aim of this study was to investigate the CYR61-related mechanisms leading to the acquisition of metastatic capacity by osteosarcoma cells.MethodsTranscriptomic data issued from RNA-seq were subjected to pathways and gene set enrichment analyses. Murine and human cell lines with overexpressed or downregulated C-terminal Binding protein 2 (CtBP2) were established by lentiviral transduction. Cell metabolic activity was assessed by Seahorse XF Analyzer; cell replication rate by BrdU incorporation assay; stemness by clonogenicity assay and RT-qPCR detection of markers; cell migration by wound healing assay and Boyden chambers system; cell invasion using Matrigel coated Boyden chambers or fluorescence microscopy of Matrigel embedded 3D spheroids. FFPE samples derived from syngeneic tumor cells grafts into BALB/c mice were analyzed by IHC. The protein interactome was predicted in silico using the STRING database.ResultsGSEA revealed that CYR61 modulate the transcription process. The in vitro expression level of CtBP2 and Cyr61 correlated positively in a panel of osteosarcoma cell lines. In silico analysis of protein-protein interaction network revealed a link with stemness markers. Variations in CtBP2 expression levels influenced stemness markers expression levels, cell clonogenicity, cell migration, Matrix Metalloproteinase activity and cell invasion. Surprisingly, while induction of CtBP2 expression under CYR61 correlated with the metastatic dissemination process in vivo, it occurred only at the invasive front of tumors. Hypoxic conditions in central tumor region interfered with CtBP2 induction of expression.ConclusionsOur findings identify for the first time that CtBP2 acts as a required critical inducing factor in the CYR61-related metastatic progression of osteosarcoma, by favoring cell migration and invasiveness. Moreover, we demonstrate that while CtBP2 is a downstream transcriptional target of CYR61 signaling cascade, it occurs only under non-hypoxic conditions. The present study suggests that CtBP2 may represent a potential pivotal target for therapeutic management of metastases spreading in osteosarcoma.

Dataset Information

The bone microenvironment invigorates metastatic seeds for further dissemination.

Publications

The bone microenvironment invigorates metastatic seeds for further dissemination.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets