title: Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth.
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 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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center.|Cancer Biology Program, Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center.|Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center.|Cancer Biology Program, Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Lowery
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center.
authors.forename: Qingling
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center.
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center.
authors.forename: Chenyu
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center.
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ellis
authors.affiliation: Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mujeeburahiman
authors.initials: M
authors.lastname: Cheerathodi
authors.affiliation: Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: McCarty
authors.affiliation: Woman's Malignancies Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Palmieri
authors.affiliation: University of Queensland Centre for Clinical Research, Herston, QLD 4029, AUS.
authors.forename: Jodi
authors.initials: J
authors.lastname: Saunus
authors.affiliation: University of Queensland Centre for Clinical Research, Herston, QLD 4029, AUS.
authors.forename: Sunil
authors.initials: S
authors.lastname: Lakhani
authors.affiliation: Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Suyun
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Aysegul A
authors.initials: AA
authors.lastname: Sahin
authors.affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.affiliation: Woman's Malignancies Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center.|Cancer Biology Program, Graduate School of Biomedical Sciences, Houston, TX 77030, USA.|Center for Molecular Medicine, China Medical University, Taichung, 40402, Taiwan.
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000556:secondary*; D002135:Calcium-Binding Proteins; D049109:Cell Proliferation / Q000235:genetics; D018932:Chemokine CCL2 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D019143:Evolution, Molecular; D055354:Exosomes / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008840:Microfilament Proteins; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: C112986:AIF1 protein, human; D002135:Calcium-Binding Proteins; D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D008840:Microfilament Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human