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Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism

Gorodetska, I.
; 
Lukiyanchuk, V.
; 
Gawin, M.
; 
Sliusar, M.
; 
Linge, A.
; 
Lohaus, F.
; 
Hölscher, T.
; 
Erdmann, K.
; 
Fuessel, S.
; 
Borkowetz, A.
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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.
Authors
Gorodetska, I.
Lukiyanchuk, V.
Gawin, M.
Sliusar, M.
Linge, A.
Lohaus, F.
Hölscher, T.
Erdmann, K.
Fuessel, S.
Borkowetz, A.
Wojakowska, A.
Fochtman, D.
Reardon, M.
Choudhury, A.
Antonelli, Y.
Leal-Egaña, A.
Köseer, A. S.
Kahya, U.
Püschel, J.
Petzold, A.
Klusa, D.
Peitzsch, C.
Kronstein-Wiedemann, R.
Tonn, T.
Marczak, L.
Thomas, C.
Widłak, P.
Pietrowska, M.
Krause, M.
Dubrovska, A.
Affiliation
OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Helmholtz-Zentrum Dresden -Rossendorf, Dresden, Germany. Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany. Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland. German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany. National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany, and Helmholtz Association/Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany. Department of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany. Institute of Bioorganic Chemistry Polish Academy of Sciences, Poznań, Poland. Division of Cancer Sciences, Translational Radiobiology Group, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation Trust, Manchester, UK. Institute for Molecular Systems Engineering and Advanced Materials, Heidelberg University, Heidelberg, Germany. Center for Regenerative Therapies Dresden (CRTD), Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany. Experimental Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany. Institute for Transfusion Medicine Dresden, German Red Cross Blood Donation Service North-East, Dresden, Germany. 2nd Department of Radiology, Medical University of Gdansk, Gdansk, Poland. OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Helmholtz-Zentrum Dresden -Rossendorf, Dresden, Germany. a.dubrovska@hzdr.de. Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany. a.dubrovska@hzdr.de. German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany. a.dubrovska@hzdr.de. German Cancer Research Center (DKFZ), Heidelberg, Germany. a.dubrovska@hzdr.de. National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany, and Helmholtz Association/Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany. a.dubrovska@hzdr.de.
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2025
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Gorodetska I, Lukiyanchuk V, Gawin M, Sliusar M, Linge A, Lohaus F, et al. 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 : CR. 2025 Mar 24;44(1):105. PubMed PMID: 40122809. Pubmed Central PMCID: PMC11931756. Epub 2025/03/24. eng.
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https://christie.openrepository.com/handle/10541/627552
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