Peroxidasin is associated with a mesenchymal-like transcriptional phenotype and promotes invasion in metastatic melanoma

Carlos C Smith-Díaz; Abhishek Kumar; Andrew Das; Paul Pace; Kenny Chitcholtan; Nicholas J Magon; Sultana Mehbuba Hossain; Michael R Eccles; Christine C Winterbourn; Martina Paumann-Page

doi:10.1016/j.freeradbiomed.2025.01.007

Peroxidasin is associated with a mesenchymal-like transcriptional phenotype and promotes invasion in metastatic melanoma

Free Radic Biol Med. 2025 Jan 8:S0891-5849(25)00007-3. doi: 10.1016/j.freeradbiomed.2025.01.007. Online ahead of print.

Affiliations

¹ Mātai Hāora, Centre for Redox Biology and Medicine, University of Otago Christchurch, Christchurch, New Zealand.
² Centre for Protein Research, Research Infrastructure Centre, University of Otago, Dunedin, New Zealand.
³ Department of Obstetrics and Gynaecology, University of Otago Christchurch, Christchurch, New Zealand.
⁴ Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.
⁵ Mātai Hāora, Centre for Redox Biology and Medicine, University of Otago Christchurch, Christchurch, New Zealand. Electronic address: martina.paumann-page@otago.ac.nz.

PMID: 39793908
DOI: 10.1016/j.freeradbiomed.2025.01.007

Abstract

Cutaneous melanoma is a highly invasive, heterogeneous and treatment resistant cancer. It's ability to dynamically shift between transcriptional states or phenotypes results in an adaptive cell plasticity that may drive cancer cell invasion or the development of therapy resistance. The expression of peroxidasin (PXDN), an extracellular matrix peroxidase, has been proposed to be associated with the invasive metastatic melanoma phenotype. We have confirmed this association by analysing the transcriptomes of 70 metastatic melanoma cell lines with variable levels of PXDN expression. This analysis highlighted a strong association between high PXDN expression and the undifferentiated invasive melanoma phenotype. To assess the functional role of PXDN in melanoma invasion, we performed a knockout of PXDN in a highly invasive cell line (NZM40). PXDN knockout decreased the invasive potential by ∼50% and decreased the expression of epithelial-mesenchymal transition and invasive marker genes as determined by RNAseq and substantiated by proteomics analysis. Bioinformatics analysis of differentially expressed genes following PXDN knockout highlighted decreases in genes linked to extracellular matrix formation, organisation and degradation as well as signalling pathways such as the WNT pathway. This study provides compelling evidence that PXDN plays a functional role in melanoma invasion by promoting an invasive, mesenchymal-like transcriptional phenotype.

Keywords: RNAseq; cancer cell invasion; epithelial mesenchymal transition; hypobromous acid; metastatic melanoma; peroxidasin; phenotype plasticity; proteomics.