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

• Published in: Nature (London) 2015-11, Vol.527 (7576), p.100-104
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 631/67/1059/602; 631/67/1347; 631/67/322; 631/67/327; 631/80/458; Adaptation, Physiological - genetics; Animals; Apoptosis; Astrocytes - cytology; Astrocytes - metabolism; Binding sites; Brain; Brain - metabolism; Brain - pathology; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - secondary; Breast cancer; Cell Proliferation - genetics; Chemokine CCL2 - secretion; Disease susceptibility; DNA-Binding Proteins - metabolism; Down-Regulation - genetics; Evolution, Molecular; Exosomes - genetics; Exosomes - metabolism; Exosomes - secretion; Female; Fibroblasts; Gene expression; Gene Expression Regulation, Neoplastic; Gene mutations; Gene Silencing; Genes, Tumor Suppressor; Genetic aspects; Health aspects; Humanities and Social Sciences; Humans; Identification and classification; letter; Male; Metastasis; Mice; Microenvironments; MicroRNAs; MicroRNAs - genetics; multidisciplinary; Mutation; Phosphorylation; Proteins; PTEN Phosphohydrolase - deficiency; PTEN Phosphohydrolase - genetics; RNA, Messenger - analysis; RNA, Messenger - genetics; Science; Tumor Microenvironment - genetics; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature15376

Expression of the tumour suppressor PTEN in disseminated primary tumour cells is lost after tumour cells metastasize to the brain, with downregulation instigated by microRNAs from astrocytes, which are transferred from cell to cell by exosomes; these findings reveal the dynamic nature of metastatic cancer cells when adapting to a new tissue environment. Adaptability of metastatic cancer cells Post-metastasis, cancer cells of common origin need to activate distinct gene expression patterns in order to adapt to a new environment. However, it is not clear when and how these adaptations to the microenvironment occur. Here, Dihua Yu and colleagues determine that tumor cell expression of the PTEN tumour suppressor is lost when these invading cells enter the brain. Downregulation of PTEN is instigated by astrocytic microRNAs, which are transferred from cell to cell through exosomes. These findings reveal the dynamic nature of metastatic cancer cells when adapting to a new tissue environment. 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 1 . Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs 2 . Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth 3 , 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