TY - JOUR
T1 - Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth
AU - Zhang, Lin
AU - Zhang, Siyuan
AU - Yao, Jun
AU - Lowery, Frank J.
AU - Zhang, Qingling
AU - Huang, Wen Chien
AU - Li, Ping
AU - Li, Min
AU - Wang, Xiao
AU - Zhang, Chenyu
AU - Wang, Hai
AU - Ellis, Kenneth
AU - Cheerathodi, Mujeeburahiman
AU - McCarty, Joseph H.
AU - Palmieri, Diane
AU - Saunus, Jodi
AU - Lakhani, Sunil
AU - Huang, Suyun
AU - Sahin, Aysegul A.
AU - Aldape, Kenneth D.
AU - Steeg, Patricia S.
AU - Yu, Dihua
N1 - Funding Information:
Acknowledgements We thank M.-C. Hung, H.-K. Lin and Z. Lu for reading the manuscript, A. Yung for PTEN promoter constructs, MD Anderson Cancer Center (MDACC) shRNA and ORFome, FACS, histology and high-resolution electron microscopy support, the animal core facilities (NIH CA16672) for technical support, and members of the Yu laboratory for helpful discussions. Thanks to A. Matsika for histological review and tissue microarray construction. This work was supported partially by DOD Center of Excellence grant (P.S.S.) subproject W81XWH-06-2-0033 (D.Y.), NIH Pathway to Independence Award 5R00CA158066-05 (S.Z.), DOD Postdoctoral Fellowship W81XWH-11-1-0003 (C.Z.), Isaiah Fidler Fellowship in Cancer Metastasis (F.J.L.), PO1-CA099031 project 4 (D.Y.), RO1-CA112567-06 (D.Y.), R01CA184836 (D.Y.), Susan G. Komen Breast Cancer Foundation Promise Grant KG091020 (D.Y.), METAvivor Research Grant (D.Y.), Breast and Ovarian Cancers Moon Shot program, China Medical University Research Fund, and Sowell-Huggins Pre-doctoral Fellowship (L.Z.) and Professorship (D.Y.) in Cancer Research. D.Y. is the Hubert L. & Olive Stringer Distinguished Chair in Basic Science at the MDACC.
Publisher Copyright:
© 2015 Macmillan Publishers Limited.All rights reserved.
PY - 2015/11/5
Y1 - 2015/11/5
N2 - 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 sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth. 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.
AB - 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 sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth. 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.
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U2 - 10.1038/nature15376
DO - 10.1038/nature15376
M3 - Article
C2 - 26479035
AN - SCOPUS:84946559154
SN - 0028-0836
VL - 527
SP - 100
EP - 104
JO - Nature
JF - Nature
IS - 7576
ER -