TY  - JOUR
AU  - Gorodetska, Ielizaveta
AU  - Lukiyanchuk, Vasyl
AU  - Gawin, Marta
AU  - Sliusar, Myroslava
AU  - Linge, Annett
AU  - Lohaus, Fabian
AU  - Hölscher, Tobias
AU  - Erdmann, Kati
AU  - Fuessel, Susanne
AU  - Borkowetz, Angelika
AU  - Wojakowska, Anna
AU  - Fochtman, Daniel
AU  - Reardon, Mark
AU  - Choudhury, Ananya
AU  - Antonelli, Yasmin
AU  - Leal-Egaña, Aldo
AU  - Köseer, Ayse Sedef
AU  - Kahya, Uğur
AU  - Püschel, Jakob
AU  - Petzold, Andrea
AU  - Klusa, Daria
AU  - Peitzsch, Claudia
AU  - Kronstein-Wiedemann, Romy
AU  - Tonn, Torsten
AU  - Marczak, Lukasz
AU  - Thomas, Christian
AU  - Widłak, Piotr
AU  - Pietrowska, Monika
AU  - Krause, Mechthild
AU  - Dubrovska, Anna
TI  - Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism.
JO  - Journal of experimental & clinical cancer research
VL  - 44
IS  - 1
SN  - 0392-9078
CY  - Heidelberg
PB  - Springer
M1  - DKFZ-2025-00610
SP  - 105
PY  - 2025
AB  - 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.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.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.TGFB1/MMP11 signaling contributes to the ALDH1A1-driven PCa metastases. MMP11 is a promising blood-based biomarker of PCa progression.
KW  - Humans
KW  - Male
KW  - Prostatic Neoplasms: pathology
KW  - Prostatic Neoplasms: genetics
KW  - Prostatic Neoplasms: metabolism
KW  - Aldehyde Dehydrogenase 1 Family: metabolism
KW  - Aldehyde Dehydrogenase 1 Family: genetics
KW  - Retinal Dehydrogenase: metabolism
KW  - Retinal Dehydrogenase: genetics
KW  - Biomarkers, Tumor: metabolism
KW  - Biomarkers, Tumor: genetics
KW  - Signal Transduction
KW  - Transforming Growth Factor beta1: metabolism
KW  - Transforming Growth Factor beta1: genetics
KW  - Matrix Metalloproteinase 11: metabolism
KW  - Matrix Metalloproteinase 11: genetics
KW  - Disease Progression
KW  - Cell Line, Tumor
KW  - Gene Expression Regulation, Neoplastic
KW  - ALDH1A1 (Other)
KW  - Liquid biopsy (Other)
KW  - MMP11 (Other)
KW  - Metastasis (Other)
KW  - Prostate cancer (Other)
KW  - TGF-β1 (Other)
KW  - Aldehyde Dehydrogenase 1 Family (NLM Chemicals)
KW  - Retinal Dehydrogenase (NLM Chemicals)
KW  - Biomarkers, Tumor (NLM Chemicals)
KW  - ALDH1A1 protein, human (NLM Chemicals)
KW  - Transforming Growth Factor beta1 (NLM Chemicals)
KW  - Matrix Metalloproteinase 11 (NLM Chemicals)
KW  - TGFB1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40122809
DO  - DOI:10.1186/s13046-025-03299-6
UR  - https://inrepo02.dkfz.de/record/300112
ER  -