title: Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts.
abstract: It is established that the interaction between microenvironment and cancer cells has a critical role in tumor development, given the dependence of neoplastic cells on stromal support. However, how this communication promotes the activation of normal (NFs) into cancer-associated fibroblasts (CAFs) is still not well understood. Most microRNA (miRNA) studies focused on tumor cell, but there is increasing evidence of their involvement in reprogramming NFs into CAFs. Here we show that miR-9, upregulated in various breast cancer cell lines and identified as pro-metastatic miRNA, affects the properties of human breast fibroblasts, enhancing the switch to CAF phenotype, thus contributing to tumor growth. Expressed at higher levels in primary triple-negative breast CAFs versus NFs isolated from patients, miR-9 improves indeed migration and invasion capabilities when transfected in immortalized NFs; viceversa, these properties are strongly impaired in CAFs upon miR-9 inhibition. We also demonstrate that tumor-secreted miR-9 can be transferred via exosomes to recipient NFs and this uptake results in enhanced cell motility. Moreover, we observed that this miRNA is also secreted by fibroblasts and in turn able to alter tumor cell behavior, by modulating its direct target E-cadherin, and NFs themselves. Consistently with the biological effects observed, gene expression profiles of NFs upon transient transfection with miR-9 show the modulation of genes mainly involved in cell motility and extracellular matrix remodeling pathways. Finally, we were able to confirm the capability of NFs transiently transfected with miR-9 to promote in vivo tumor growth. Taken together, these data provide new insights into the role of miR-9 as an important player in the cross-talk between cancer cells and stroma.
authors.affiliation: Start Up Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Amadeo 42 Road, Milan 20133, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Baroni
authors.affiliation: INMGEN, Periferico Sur 4809, Arenal Tepepan, Tlalpan, Mexico City 14610, Mexico.
authors.forename: S
authors.initials: S
authors.lastname: Romero-Cordoba
authors.affiliation: Start Up Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Amadeo 42 Road, Milan 20133, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Plantamura
authors.affiliation: Functional Genomics and Bioinformatics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Amadeo 42 Road, Milan 20133, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Dugo
authors.affiliation: Start Up Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Amadeo 42 Road, Milan 20133, Italy.
authors.forename: E
authors.initials: E
authors.lastname: D'Ippolito
authors.affiliation: Start Up Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Amadeo 42 Road, Milan 20133, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cataldo
authors.affiliation: Start Up Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Amadeo 42 Road, Milan 20133, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Cosentino
authors.affiliation: Biomarkers Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Amadeo 42 Road, Milan 20133, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Angeloni
authors.affiliation: Unit of Immunotherapy and Anticancer Innovative Therapeutics, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Venezian 1 Road, Milan 20133, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rossini
authors.affiliation: Biomarkers Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Amadeo 42 Road, Milan 20133, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Daidone
authors.affiliation: Start Up Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Amadeo 42 Road, Milan 20133, Italy.
authors.forename: M V
authors.initials: MV
authors.lastname: Iorio
mesh_terms: D000818:Animals; D001940:Breast / Q000378:metabolism* / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism*; D010641:Phenotype; D059467:Transcriptome; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: D015820:Cadherins; C541874:MIRN92 microRNA, human; D035683:MicroRNAs