Fibroblasts activated by miRs-185-5p, miR-652-5p, and miR-1246 shape the tumor microenvironment in triple-negative breast cancer via PATZ1 downregulation
Abstract The intricate interplay between epithelial and fibroblast cells within the tumor microenvironment plays a crucial role in driving triple-negative breast cancer progression. This crosstalk involves the exchange of various signaling molecules, including growth factors, cytokines, extracellula...
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2025-07-01
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| Series: | Cellular and Molecular Life Sciences |
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| Online Access: | https://doi.org/10.1007/s00018-025-05781-y |
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| author | Giada De Luca Gianluca Petrillo Iolanda Scognamiglio Katia Pane Lorenza Cocca Giuseppina Roscigno Martina Mascolo Claudia Pignataro Sara Verde Aurelia Fraticelli Danilo Fiore Alessandra Affinito Silvia Nuzzo Zoran Minic Francesca De Micco Guglielmo Thomas Monica Franzese Maxim V. Berezovski Monica Fedele Gerolama Condorelli Cristina Quintavalle |
| author_facet | Giada De Luca Gianluca Petrillo Iolanda Scognamiglio Katia Pane Lorenza Cocca Giuseppina Roscigno Martina Mascolo Claudia Pignataro Sara Verde Aurelia Fraticelli Danilo Fiore Alessandra Affinito Silvia Nuzzo Zoran Minic Francesca De Micco Guglielmo Thomas Monica Franzese Maxim V. Berezovski Monica Fedele Gerolama Condorelli Cristina Quintavalle |
| author_sort | Giada De Luca |
| collection | DOAJ |
| description | Abstract The intricate interplay between epithelial and fibroblast cells within the tumor microenvironment plays a crucial role in driving triple-negative breast cancer progression. This crosstalk involves the exchange of various signaling molecules, including growth factors, cytokines, extracellular matrix components, and extracellular vesicles. Recently, we demonstrated that triple-negative breast cancer extracellular vesicles carry and release a specific combination of miRs, including miR-185-5p, miR-652-5p, and miR-1246 (from here on, referred as combo-miRs), into normal fibroblasts, effectively reprogramming them into cancer-associated fibroblasts. Here, we show that the conditioned medium from the fibroblasts activated by combo-miRs exerts a pro-tumorigenic effect on epithelial cells, enhancing the viability and migratory potential while driving increased invasiveness in patient-derived breast cancer organoids. A proteomic analysis of conditioned medium from combo-miRs activated fibroblasts revealed 76 significantly upregulated secreted proteins compared to control. Bioinformatic analysis identified the transcriptional factor PATZ1 as a potential regulator of the 12 most highly upregulated proteins. Consistently, in-silico predictions and in vitro experiments confirmed that PATZ1 is a direct target of miR-185-5p and miR-652-5p. The downregulation of PATZ1 by these miRNAs led to increased levels of the secreted proteins in the conditioned medium from combo-miRs activated fibroblasts. Furthermore, the conditioned medium from PATZ1-knockout mesenchymal embryonic fibroblasts and normal fibroblasts with silenced PATZ1 similarly enhanced the migratory potential of MCF10A cells, further supporting the critical role of PATZ1 in regulating tumor-promoting mechanisms. These findings provide valuable insights into the dynamics of the TME in TNBC, highlighting combo-miRs and PATZ1 as promising targets for future therapeutic interventions. Graphical Abstract |
| format | Article |
| id | doaj-art-db45b8f49b9a485489a4241e2f6f9902 |
| institution | Kabale University |
| issn | 1420-9071 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Springer |
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| series | Cellular and Molecular Life Sciences |
| spelling | doaj-art-db45b8f49b9a485489a4241e2f6f99022025-08-20T03:42:44ZengSpringerCellular and Molecular Life Sciences1420-90712025-07-0182111910.1007/s00018-025-05781-yFibroblasts activated by miRs-185-5p, miR-652-5p, and miR-1246 shape the tumor microenvironment in triple-negative breast cancer via PATZ1 downregulationGiada De Luca0Gianluca Petrillo1Iolanda Scognamiglio2Katia Pane3Lorenza Cocca4Giuseppina Roscigno5Martina Mascolo6Claudia Pignataro7Sara Verde8Aurelia Fraticelli9Danilo Fiore10Alessandra Affinito11Silvia Nuzzo12Zoran Minic13Francesca De Micco14Guglielmo Thomas15Monica Franzese16Maxim V. Berezovski17Monica Fedele18Gerolama Condorelli19Cristina Quintavalle20Institute of Endotypes in Oncology, Metabolism and Immunology “G. Salvatore” (IEOMI), Consiglio Nazionale delle Ricerche (CNR)Department of Molecular Medicine and Medical Biotechnology, “Federico II” University of NaplesDepartment of Molecular Medicine and Medical Biotechnology, “Federico II” University of NaplesIRCCS SYNLAB SDNDepartment of Molecular Medicine and Medical Biotechnology, “Federico II” University of NaplesDepartment of Molecular Medicine and Medical Biotechnology, “Federico II” University of NaplesDepartment of Molecular Medicine and Medical Biotechnology, “Federico II” University of NaplesDepartment of Molecular Medicine and Medical Biotechnology, “Federico II” University of NaplesDepartment of Biomedicine and Prevention, University of Rome “Tor Vergata”Department of Biomedicine and Prevention, University of Rome “Tor Vergata”Institute of Endotypes in Oncology, Metabolism and Immunology “G. Salvatore” (IEOMI), Consiglio Nazionale delle Ricerche (CNR)Department of Molecular Medicine and Medical Biotechnology, “Federico II” University of NaplesIRCCS SYNLAB SDNDepartment of Chemistry and Biomolecular Sciences and John L. Holmes Mass Spectrometry Facility, University of OttawaMediterranea CardiocentroMediterranea CardiocentroIRCCS SYNLAB SDNDepartment of Chemistry and Biomolecular Sciences and John L. Holmes Mass Spectrometry Facility, University of OttawaInstitute of Endotypes in Oncology, Metabolism and Immunology “G. Salvatore” (IEOMI), Consiglio Nazionale delle Ricerche (CNR)Institute of Endotypes in Oncology, Metabolism and Immunology “G. Salvatore” (IEOMI), Consiglio Nazionale delle Ricerche (CNR)Institute of Endotypes in Oncology, Metabolism and Immunology “G. Salvatore” (IEOMI), Consiglio Nazionale delle Ricerche (CNR)Abstract The intricate interplay between epithelial and fibroblast cells within the tumor microenvironment plays a crucial role in driving triple-negative breast cancer progression. This crosstalk involves the exchange of various signaling molecules, including growth factors, cytokines, extracellular matrix components, and extracellular vesicles. Recently, we demonstrated that triple-negative breast cancer extracellular vesicles carry and release a specific combination of miRs, including miR-185-5p, miR-652-5p, and miR-1246 (from here on, referred as combo-miRs), into normal fibroblasts, effectively reprogramming them into cancer-associated fibroblasts. Here, we show that the conditioned medium from the fibroblasts activated by combo-miRs exerts a pro-tumorigenic effect on epithelial cells, enhancing the viability and migratory potential while driving increased invasiveness in patient-derived breast cancer organoids. A proteomic analysis of conditioned medium from combo-miRs activated fibroblasts revealed 76 significantly upregulated secreted proteins compared to control. Bioinformatic analysis identified the transcriptional factor PATZ1 as a potential regulator of the 12 most highly upregulated proteins. Consistently, in-silico predictions and in vitro experiments confirmed that PATZ1 is a direct target of miR-185-5p and miR-652-5p. The downregulation of PATZ1 by these miRNAs led to increased levels of the secreted proteins in the conditioned medium from combo-miRs activated fibroblasts. Furthermore, the conditioned medium from PATZ1-knockout mesenchymal embryonic fibroblasts and normal fibroblasts with silenced PATZ1 similarly enhanced the migratory potential of MCF10A cells, further supporting the critical role of PATZ1 in regulating tumor-promoting mechanisms. These findings provide valuable insights into the dynamics of the TME in TNBC, highlighting combo-miRs and PATZ1 as promising targets for future therapeutic interventions. Graphical Abstracthttps://doi.org/10.1007/s00018-025-05781-yFibroblastsCAFsmiRNAsExtracellular vesiclesPATZ1 |
| spellingShingle | Giada De Luca Gianluca Petrillo Iolanda Scognamiglio Katia Pane Lorenza Cocca Giuseppina Roscigno Martina Mascolo Claudia Pignataro Sara Verde Aurelia Fraticelli Danilo Fiore Alessandra Affinito Silvia Nuzzo Zoran Minic Francesca De Micco Guglielmo Thomas Monica Franzese Maxim V. Berezovski Monica Fedele Gerolama Condorelli Cristina Quintavalle Fibroblasts activated by miRs-185-5p, miR-652-5p, and miR-1246 shape the tumor microenvironment in triple-negative breast cancer via PATZ1 downregulation Cellular and Molecular Life Sciences Fibroblasts CAFs miRNAs Extracellular vesicles PATZ1 |
| title | Fibroblasts activated by miRs-185-5p, miR-652-5p, and miR-1246 shape the tumor microenvironment in triple-negative breast cancer via PATZ1 downregulation |
| title_full | Fibroblasts activated by miRs-185-5p, miR-652-5p, and miR-1246 shape the tumor microenvironment in triple-negative breast cancer via PATZ1 downregulation |
| title_fullStr | Fibroblasts activated by miRs-185-5p, miR-652-5p, and miR-1246 shape the tumor microenvironment in triple-negative breast cancer via PATZ1 downregulation |
| title_full_unstemmed | Fibroblasts activated by miRs-185-5p, miR-652-5p, and miR-1246 shape the tumor microenvironment in triple-negative breast cancer via PATZ1 downregulation |
| title_short | Fibroblasts activated by miRs-185-5p, miR-652-5p, and miR-1246 shape the tumor microenvironment in triple-negative breast cancer via PATZ1 downregulation |
| title_sort | fibroblasts activated by mirs 185 5p mir 652 5p and mir 1246 shape the tumor microenvironment in triple negative breast cancer via patz1 downregulation |
| topic | Fibroblasts CAFs miRNAs Extracellular vesicles PATZ1 |
| url | https://doi.org/10.1007/s00018-025-05781-y |
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