Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth

Zhang, Lin, Zhang, Siyuan, Yao, Jun, Lowery, Frank J., Zhang, Qingling, Huang, Wen-Chien, Li, Ping, Li, Min, Wang, Xiao, Zhang, Chenyu, Wang, Hai, Ellis, Kenneth, Cheerathodi, Mujeeburahiman, McCarty, Joseph H., Palmieri, Diane, Saunus, Jodi, Lakhani, Sunil, Huang, Suyun, Sahin, Aysegul A., Aldape, Kenneth D., Steeg, Patricia S. and Yu, Dihua (2015) Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature, 527 7576: 100-104. doi:10.1038/nature15376

Author Zhang, Lin
Zhang, Siyuan
Yao, Jun
Lowery, Frank J.
Zhang, Qingling
Huang, Wen-Chien
Li, Ping
Li, Min
Wang, Xiao
Zhang, Chenyu
Wang, Hai
Ellis, Kenneth
Cheerathodi, Mujeeburahiman
McCarty, Joseph H.
Palmieri, Diane
Saunus, Jodi
Lakhani, Sunil
Huang, Suyun
Sahin, Aysegul A.
Aldape, Kenneth D.
Steeg, Patricia S.
Yu, Dihua
Title Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth
Journal name Nature   Check publisher's open access policy
ISSN 1476-4687
Publication date 2015-11-05
Sub-type Article (original research)
DOI 10.1038/nature15376
Open Access Status Not Open Access
Volume 527
Issue 7576
Start page 100
End page 104
Total pages 5
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2016
Language eng
Formatted abstract
The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells’ adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites1. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs2. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth3,4. Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumour cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2016 Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 40 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 45 times in Scopus Article | Citations
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