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...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2016-07-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/cddis.2016.224 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832585389003505664 |
|---|---|
| author | Sara Baroni S Romero-Cordoba I Plantamura M Dugo E D’Ippolito A Cataldo G Cosentino V Angeloni A Rossini M G Daidone M V Iorio |
| author_facet | Sara Baroni S Romero-Cordoba I Plantamura M Dugo E D’Ippolito A Cataldo G Cosentino V Angeloni A Rossini M G Daidone M V Iorio |
| author_sort | Sara Baroni |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d8bde3ede4a543cb9054ac768091af55 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2016-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-d8bde3ede4a543cb9054ac768091af552025-01-26T12:54:37ZengNature Publishing GroupCell Death and Disease2041-48892016-07-0177e2312e231210.1038/cddis.2016.224Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblastsSara Baroni0S Romero-Cordoba1I Plantamura2M Dugo3E D’Ippolito4A Cataldo5G Cosentino6V Angeloni7A Rossini8M G Daidone9M V Iorio10Department of Experimental Oncology and Molecular Medicine, Start Up Unit, Fondazione IRCCS Istituto Nazionale dei TumoriINMGEN, Periferico Sur 4809, Arenal TepepanDepartment of Experimental Oncology and Molecular Medicine, Start Up Unit, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Experimental Oncology and Molecular Medicine, Functional Genomics and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Experimental Oncology and Molecular Medicine, Start Up Unit, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Experimental Oncology and Molecular Medicine, Start Up Unit, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Experimental Oncology and Molecular Medicine, Start Up Unit, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Experimental Oncology and Molecular Medicine, Biomarkers Unit, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Medical Oncology, Unit of Immunotherapy and Anticancer Innovative Therapeutics, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Experimental Oncology and Molecular Medicine, Biomarkers Unit, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Experimental Oncology and Molecular Medicine, Start Up Unit, Fondazione IRCCS Istituto Nazionale dei TumoriAbstract 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.https://doi.org/10.1038/cddis.2016.224 |
| spellingShingle | Sara Baroni S Romero-Cordoba I Plantamura M Dugo E D’Ippolito A Cataldo G Cosentino V Angeloni A Rossini M G Daidone M V Iorio Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts Cell Death and Disease |
| title | Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts |
| title_full | Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts |
| title_fullStr | Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts |
| title_full_unstemmed | Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts |
| title_short | Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts |
| title_sort | exosome mediated delivery of mir 9 induces cancer associated fibroblast like properties in human breast fibroblasts |
| url | https://doi.org/10.1038/cddis.2016.224 |
| work_keys_str_mv | AT sarabaroni exosomemediateddeliveryofmir9inducescancerassociatedfibroblastlikepropertiesinhumanbreastfibroblasts AT sromerocordoba exosomemediateddeliveryofmir9inducescancerassociatedfibroblastlikepropertiesinhumanbreastfibroblasts AT iplantamura exosomemediateddeliveryofmir9inducescancerassociatedfibroblastlikepropertiesinhumanbreastfibroblasts AT mdugo exosomemediateddeliveryofmir9inducescancerassociatedfibroblastlikepropertiesinhumanbreastfibroblasts AT edippolito exosomemediateddeliveryofmir9inducescancerassociatedfibroblastlikepropertiesinhumanbreastfibroblasts AT acataldo exosomemediateddeliveryofmir9inducescancerassociatedfibroblastlikepropertiesinhumanbreastfibroblasts AT gcosentino exosomemediateddeliveryofmir9inducescancerassociatedfibroblastlikepropertiesinhumanbreastfibroblasts AT vangeloni exosomemediateddeliveryofmir9inducescancerassociatedfibroblastlikepropertiesinhumanbreastfibroblasts AT arossini exosomemediateddeliveryofmir9inducescancerassociatedfibroblastlikepropertiesinhumanbreastfibroblasts AT mgdaidone exosomemediateddeliveryofmir9inducescancerassociatedfibroblastlikepropertiesinhumanbreastfibroblasts AT mviorio exosomemediateddeliveryofmir9inducescancerassociatedfibroblastlikepropertiesinhumanbreastfibroblasts |