Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism
Abstract Background Prostate cancer (PCa) is the second most common type of tumor diagnosed in men and the fifth leading cause of cancer-related death in male patients. The response of metastatic disease to standard treatment is heterogeneous. As for now, there is no curative treatment option availa...
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2025-03-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03299-6 |
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| author | Ielizaveta Gorodetska Vasyl Lukiyanchuk Marta Gawin Myroslava Sliusar Annett Linge Fabian Lohaus Tobias Hölscher Kati Erdmann Susanne Fuessel Angelika Borkowetz Anna Wojakowska Daniel Fochtman Mark Reardon Ananya Choudhury Yasmin Antonelli Aldo Leal-Egaña Ayse Sedef Köseer Uğur Kahya Jakob Püschel Andrea Petzold Daria Klusa Claudia Peitzsch Romy Kronstein-Wiedemann Torsten Tonn Lukasz Marczak Christian Thomas Piotr Widłak Monika Pietrowska Mechthild Krause Anna Dubrovska |
| author_facet | Ielizaveta Gorodetska Vasyl Lukiyanchuk Marta Gawin Myroslava Sliusar Annett Linge Fabian Lohaus Tobias Hölscher Kati Erdmann Susanne Fuessel Angelika Borkowetz Anna Wojakowska Daniel Fochtman Mark Reardon Ananya Choudhury Yasmin Antonelli Aldo Leal-Egaña Ayse Sedef Köseer Uğur Kahya Jakob Püschel Andrea Petzold Daria Klusa Claudia Peitzsch Romy Kronstein-Wiedemann Torsten Tonn Lukasz Marczak Christian Thomas Piotr Widłak Monika Pietrowska Mechthild Krause Anna Dubrovska |
| author_sort | Ielizaveta Gorodetska |
| collection | DOAJ |
| description | Abstract Background Prostate cancer (PCa) is the second most common type of tumor diagnosed in men and the fifth leading cause of cancer-related death in male patients. The response of metastatic disease to standard treatment is heterogeneous. As for now, there is no curative treatment option available for metastatic PCa, and the clinical tests capable of predicting metastatic dissemination and metastatic response to the therapies are lacking. Our recent study identified aldehyde dehydrogenases ALDH1A1 and ALDH1A3 as critical regulators of PCa metastases. Still, the exact mechanisms mediating the role of these proteins in PCa metastatic dissemination remain not fully understood, and plasma-based biomarkers of these metastatic mechanisms are not available. Methods Genetic silencing, gene overexpression, or treatment with different concentrations of the retinoic acid (RA) isomers, which are the products of ALDH catalytic activity, were used to modulate the interplay between retinoic acid receptors (RARs) and androgen receptor (AR). RNA sequencing (RNAseq), reporter gene assays, and chromatin immunoprecipitation (ChIP) analysis were employed to validate the role of RARs and AR in the regulation of the transforming growth factor-beta 1 (TGFB1) expression. Gene expression levels of ALDH1A1, ALDH1A3, and the matrix metalloproteinase 11 (MMP11) and their correlation with pathological parameters and clinical outcomes were analysed by mining several publicly available patient datasets as well as our multi-center transcriptomic dataset from patients with high-risk and locally advanced PCa. The level of MMP11 protein was analysed by enzyme-linked immunosorbent assay (ELISA) in independent cohorts of plasma samples from patients with primary or metastatic PCa and healthy donors, while plasma proteome profiles were obtained for selected subsets of PCa patients. Results We could show that ALDH1A1 and ALDH1A3 genes differently regulate TGFB1 expression in a RAR- and AR-dependent manner. We further observed that the TGF-β1 pathway contributes to the regulation of the MMPs, including MMP11. We have confirmed the relevance of MMP11 as a promising clinical marker for PCa using several independent gene expression datasets. Further, we have validated plasma MMP11 level as a prognostic biomarker in patients with metastatic PCa. Finally, we proposed a hypothetical ALDH1A1/MMP11-related plasma proteome-based prognostic signature. Conclusions TGFB1/MMP11 signaling contributes to the ALDH1A1-driven PCa metastases. MMP11 is a promising blood-based biomarker of PCa progression. |
| format | Article |
| id | doaj-art-39ad058654cc4db59d1c3aa2bbba94b4 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-39ad058654cc4db59d1c3aa2bbba94b42025-08-20T03:40:45ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-03-0144112510.1186/s13046-025-03299-6Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanismIelizaveta Gorodetska0Vasyl Lukiyanchuk1Marta Gawin2Myroslava Sliusar3Annett Linge4Fabian Lohaus5Tobias Hölscher6Kati Erdmann7Susanne Fuessel8Angelika Borkowetz9Anna Wojakowska10Daniel Fochtman11Mark Reardon12Ananya Choudhury13Yasmin Antonelli14Aldo Leal-Egaña15Ayse Sedef Köseer16Uğur Kahya17Jakob Püschel18Andrea Petzold19Daria Klusa20Claudia Peitzsch21Romy Kronstein-Wiedemann22Torsten Tonn23Lukasz Marczak24Christian Thomas25Piotr Widłak26Monika Pietrowska27Mechthild Krause28Anna Dubrovska29OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of TechnologyOncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of TechnologyCenter for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice BranchOncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of TechnologyOncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of TechnologyOncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of TechnologyOncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of TechnologyGerman Cancer Consortium (DKTK)German Cancer Consortium (DKTK)German Cancer Consortium (DKTK)Institute of Bioorganic Chemistry Polish Academy of SciencesInstitute of Bioorganic Chemistry Polish Academy of SciencesDivision of Cancer Sciences, Translational Radiobiology Group, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation TrustDivision of Cancer Sciences, Translational Radiobiology Group, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation TrustInstitute for Molecular Systems Engineering and Advanced Materials, Heidelberg UniversityInstitute for Molecular Systems Engineering and Advanced Materials, Heidelberg UniversityOncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of TechnologyOncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of TechnologyOncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of TechnologyOncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of TechnologyOncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of TechnologyOncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of TechnologyExperimental Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of TechnologyGerman Cancer Consortium (DKTK)Institute of Bioorganic Chemistry Polish Academy of SciencesGerman Cancer Consortium (DKTK)2nd Department of Radiology, Medical University of GdanskCenter for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice BranchOncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of TechnologyOncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of TechnologyAbstract Background Prostate cancer (PCa) is the second most common type of tumor diagnosed in men and the fifth leading cause of cancer-related death in male patients. The response of metastatic disease to standard treatment is heterogeneous. As for now, there is no curative treatment option available for metastatic PCa, and the clinical tests capable of predicting metastatic dissemination and metastatic response to the therapies are lacking. Our recent study identified aldehyde dehydrogenases ALDH1A1 and ALDH1A3 as critical regulators of PCa metastases. Still, the exact mechanisms mediating the role of these proteins in PCa metastatic dissemination remain not fully understood, and plasma-based biomarkers of these metastatic mechanisms are not available. Methods Genetic silencing, gene overexpression, or treatment with different concentrations of the retinoic acid (RA) isomers, which are the products of ALDH catalytic activity, were used to modulate the interplay between retinoic acid receptors (RARs) and androgen receptor (AR). RNA sequencing (RNAseq), reporter gene assays, and chromatin immunoprecipitation (ChIP) analysis were employed to validate the role of RARs and AR in the regulation of the transforming growth factor-beta 1 (TGFB1) expression. Gene expression levels of ALDH1A1, ALDH1A3, and the matrix metalloproteinase 11 (MMP11) and their correlation with pathological parameters and clinical outcomes were analysed by mining several publicly available patient datasets as well as our multi-center transcriptomic dataset from patients with high-risk and locally advanced PCa. The level of MMP11 protein was analysed by enzyme-linked immunosorbent assay (ELISA) in independent cohorts of plasma samples from patients with primary or metastatic PCa and healthy donors, while plasma proteome profiles were obtained for selected subsets of PCa patients. Results We could show that ALDH1A1 and ALDH1A3 genes differently regulate TGFB1 expression in a RAR- and AR-dependent manner. We further observed that the TGF-β1 pathway contributes to the regulation of the MMPs, including MMP11. We have confirmed the relevance of MMP11 as a promising clinical marker for PCa using several independent gene expression datasets. Further, we have validated plasma MMP11 level as a prognostic biomarker in patients with metastatic PCa. Finally, we proposed a hypothetical ALDH1A1/MMP11-related plasma proteome-based prognostic signature. Conclusions TGFB1/MMP11 signaling contributes to the ALDH1A1-driven PCa metastases. MMP11 is a promising blood-based biomarker of PCa progression.https://doi.org/10.1186/s13046-025-03299-6Prostate cancerMetastasisLiquid biopsyMMP11ALDH1A1TGF-β1 |
| spellingShingle | Ielizaveta Gorodetska Vasyl Lukiyanchuk Marta Gawin Myroslava Sliusar Annett Linge Fabian Lohaus Tobias Hölscher Kati Erdmann Susanne Fuessel Angelika Borkowetz Anna Wojakowska Daniel Fochtman Mark Reardon Ananya Choudhury Yasmin Antonelli Aldo Leal-Egaña Ayse Sedef Köseer Uğur Kahya Jakob Püschel Andrea Petzold Daria Klusa Claudia Peitzsch Romy Kronstein-Wiedemann Torsten Tonn Lukasz Marczak Christian Thomas Piotr Widłak Monika Pietrowska Mechthild Krause Anna Dubrovska Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism Journal of Experimental & Clinical Cancer Research Prostate cancer Metastasis Liquid biopsy MMP11 ALDH1A1 TGF-β1 |
| title | Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism |
| title_full | Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism |
| title_fullStr | Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism |
| title_full_unstemmed | Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism |
| title_short | Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism |
| title_sort | blood based detection of mmp11 as a marker of prostate cancer progression regulated by the aldh1a1 tgf β1 signaling mechanism |
| topic | Prostate cancer Metastasis Liquid biopsy MMP11 ALDH1A1 TGF-β1 |
| url | https://doi.org/10.1186/s13046-025-03299-6 |
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