Proteomic landscape of decellularized breast carcinomas identifies C-type lectin domain family 3 member A as a driver of cancer aggressiveness
Abstract An extracellular matrix (ECM) gene expression pattern (ECM3) distinguished truly aggressive grade III breast carcinomas (BCs). Here, we examined the biomechanical characteristics of the ECM in human BCs to identify the molecules that mediate the aggressiveness of ECM3/grade III (E3G3) tumor...
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Nature Portfolio
2025-06-01
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| Series: | npj Breast Cancer |
| Online Access: | https://doi.org/10.1038/s41523-025-00769-0 |
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| author | Tiziana Triulzi Marta Giussani Elisa Maffioli Viola Regondi Ewelina J. Lorenc Valeria Arlotta Francesca Bianchi Sabina Pozzi Martina Varricchio Valeria Cancila Cesare Valenti Marco Sandri Alessandro Podestà Lucia Sfondrini Giovanni Vozzi Gabriella Tedeschi Serenella M. Pupa Elda Tagliabue |
| author_facet | Tiziana Triulzi Marta Giussani Elisa Maffioli Viola Regondi Ewelina J. Lorenc Valeria Arlotta Francesca Bianchi Sabina Pozzi Martina Varricchio Valeria Cancila Cesare Valenti Marco Sandri Alessandro Podestà Lucia Sfondrini Giovanni Vozzi Gabriella Tedeschi Serenella M. Pupa Elda Tagliabue |
| author_sort | Tiziana Triulzi |
| collection | DOAJ |
| description | Abstract An extracellular matrix (ECM) gene expression pattern (ECM3) distinguished truly aggressive grade III breast carcinomas (BCs). Here, we examined the biomechanical characteristics of the ECM in human BCs to identify the molecules that mediate the aggressiveness of ECM3/grade III (E3G3) tumors. By shotgun proteomics of decellularized human BCs, we found a significant enrichment in proteins involved in tumor-ECM interaction in E3G3 tumors. These tumors were characterized by high dense collagen deposition, a fibrillary cytoskeleton network and the highest stiffness. CLEC3A, a secreted C-type lectin domain family 3 member, was found unique of E3G3 tumors and was validated to be more expressed in these tumors by immunohistochemistry in 2 human BC cohorts, associating significantly with worse prognosis. Ectopic CLEC3A overexpression in MDA-MB-231, MDA-MB-361, and MDA-MB-468 BC cells increased intracellular mediators of tumor adhesion to the ECM, actin-stress fibers and YAP activation, and tumor migration. Accordingly, levels of the YAP/TAZ gene signature were higher in CLEC3A-positive ECM3-enriched tumors and correlated with tumor stiffness. These results implicate CLEC3A in mediating the ability of E3G3 BCs to sense cues in the surrounding ECM, accelerating tumor progression. |
| format | Article |
| id | doaj-art-68f94d90b0a646d28ca875ebae74e3d0 |
| institution | OA Journals |
| issn | 2374-4677 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Breast Cancer |
| spelling | doaj-art-68f94d90b0a646d28ca875ebae74e3d02025-08-20T02:30:43ZengNature Portfolionpj Breast Cancer2374-46772025-06-0111111310.1038/s41523-025-00769-0Proteomic landscape of decellularized breast carcinomas identifies C-type lectin domain family 3 member A as a driver of cancer aggressivenessTiziana Triulzi0Marta Giussani1Elisa Maffioli2Viola Regondi3Ewelina J. Lorenc4Valeria Arlotta5Francesca Bianchi6Sabina Pozzi7Martina Varricchio8Valeria Cancila9Cesare Valenti10Marco Sandri11Alessandro Podestà12Lucia Sfondrini13Giovanni Vozzi14Gabriella Tedeschi15Serenella M. Pupa16Elda Tagliabue17Microenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMicroenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoDepartment of Veterinary Medicine and Animal Science, Università degli Studi di MilanoMicroenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMolecular Epigenomics Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMicroenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoDepartment of Biomedical Science for Health, Università degli Studi di MilanoMicroenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMicroenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoTumor Immunology Unit, Department of Health Science, Human Pathology Section, University of Palermo School of MedicineDepartment of Mathematics and Informatics, University of PalermoMicroenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoDipartimento di Fisica “Aldo Pontremoli”, Università degli Studi di MilanoMicroenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoResearch Center E. Piaggio, University of PisaDepartment of Veterinary Medicine and Animal Science, Università degli Studi di MilanoMicroenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMicroenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoAbstract An extracellular matrix (ECM) gene expression pattern (ECM3) distinguished truly aggressive grade III breast carcinomas (BCs). Here, we examined the biomechanical characteristics of the ECM in human BCs to identify the molecules that mediate the aggressiveness of ECM3/grade III (E3G3) tumors. By shotgun proteomics of decellularized human BCs, we found a significant enrichment in proteins involved in tumor-ECM interaction in E3G3 tumors. These tumors were characterized by high dense collagen deposition, a fibrillary cytoskeleton network and the highest stiffness. CLEC3A, a secreted C-type lectin domain family 3 member, was found unique of E3G3 tumors and was validated to be more expressed in these tumors by immunohistochemistry in 2 human BC cohorts, associating significantly with worse prognosis. Ectopic CLEC3A overexpression in MDA-MB-231, MDA-MB-361, and MDA-MB-468 BC cells increased intracellular mediators of tumor adhesion to the ECM, actin-stress fibers and YAP activation, and tumor migration. Accordingly, levels of the YAP/TAZ gene signature were higher in CLEC3A-positive ECM3-enriched tumors and correlated with tumor stiffness. These results implicate CLEC3A in mediating the ability of E3G3 BCs to sense cues in the surrounding ECM, accelerating tumor progression.https://doi.org/10.1038/s41523-025-00769-0 |
| spellingShingle | Tiziana Triulzi Marta Giussani Elisa Maffioli Viola Regondi Ewelina J. Lorenc Valeria Arlotta Francesca Bianchi Sabina Pozzi Martina Varricchio Valeria Cancila Cesare Valenti Marco Sandri Alessandro Podestà Lucia Sfondrini Giovanni Vozzi Gabriella Tedeschi Serenella M. Pupa Elda Tagliabue Proteomic landscape of decellularized breast carcinomas identifies C-type lectin domain family 3 member A as a driver of cancer aggressiveness npj Breast Cancer |
| title | Proteomic landscape of decellularized breast carcinomas identifies C-type lectin domain family 3 member A as a driver of cancer aggressiveness |
| title_full | Proteomic landscape of decellularized breast carcinomas identifies C-type lectin domain family 3 member A as a driver of cancer aggressiveness |
| title_fullStr | Proteomic landscape of decellularized breast carcinomas identifies C-type lectin domain family 3 member A as a driver of cancer aggressiveness |
| title_full_unstemmed | Proteomic landscape of decellularized breast carcinomas identifies C-type lectin domain family 3 member A as a driver of cancer aggressiveness |
| title_short | Proteomic landscape of decellularized breast carcinomas identifies C-type lectin domain family 3 member A as a driver of cancer aggressiveness |
| title_sort | proteomic landscape of decellularized breast carcinomas identifies c type lectin domain family 3 member a as a driver of cancer aggressiveness |
| url | https://doi.org/10.1038/s41523-025-00769-0 |
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