Redox signalling regulates breast cancer metastasis via phenotypic and metabolic reprogramming due to p63 activation by HIF1α Journal Article
| Authors: | Ren, Z.; Dharmaratne, M.; Liang, H.; Benard, O.; Morales-Gallego, M.; Suyama, K.; Kumar, V.; Fard, A. T.; Kulkarni, A. S.; Prystowsky, M.; Mar, J. C.; Norton, L.; Hazan, R. B. |
| Article Title: | Redox signalling regulates breast cancer metastasis via phenotypic and metabolic reprogramming due to p63 activation by HIF1α |
| Abstract: | Background: Redox signaling caused by knockdown (KD) of Glutathione Peroxidase 2 (GPx2) in the PyMT mammary tumour model promotes metastasis via phenotypic and metabolic reprogramming. However, the tumour cell subpopulations and transcriptional regulators governing these processes remained unknown. Methods: We used single-cell transcriptomics to decipher the tumour cell subpopulations stimulated by GPx2 KD in the PyMT mammary tumour and paired pulmonary metastases. We analyzed the EMT spectrum across the various tumour cell clusters using pseudotime trajectory analysis and elucidated the transcriptional and metabolic regulation of the hybrid EMT state. Results: Integration of single-cell transcriptomics between the PyMT/GPx2 KD primary tumour and paired lung metastases unraveled a basal/mesenchymal-like cluster and several luminal-like clusters spanning an EMT spectrum. Interestingly, the luminal clusters at the primary tumour gained mesenchymal gene expression, resulting in epithelial/mesenchymal subpopulations fueled by oxidative phosphorylation (OXPHOS) and glycolysis. By contrast, at distant metastasis, the basal/mesenchymal-like cluster gained luminal and mesenchymal gene expression, resulting in a hybrid subpopulation using OXPHOS, supporting adaptive plasticity. Furthermore, p63 was dramatically upregulated in all hybrid clusters, implying a role in regulating partial EMT and MET at primary and distant sites, respectively. Importantly, these effects were reversed by HIF1α loss or GPx2 gain of function, resulting in metastasis suppression. Conclusions: Collectively, these results underscored a dramatic effect of redox signaling on p63 activation by HIF1α, underlying phenotypic and metabolic plasticity leading to mammary tumour metastasis. © The Author(s) 2024. |
| Keywords: | platelet derived growth factor; controlled study; primary tumor; unclassified drug; human cell; promoter region; genetics; nonhuman; comparative study; mouse; phenotype; animal; animals; animal tissue; mesenchyme cell; metastasis; hepatocyte nuclear factor 3alpha; gene expression; tumor volume; lung neoplasms; vascular cell adhesion molecule 1; animal experiment; animal model; protein; in vitro study; pathology; cell line, tumor; breast neoplasms; transcriptomics; uvomorulin; distant metastasis; lung tumor; lung metastasis; regulatory mechanism; breast tumor; tumor cell line; nerve cell adhesion molecule; cell subpopulation; vasculotropin a; tumor cell; cell isolation; neoplasm metastasis; down regulation; protein p63; upregulation; epithelial cell adhesion molecule; neoplasms, second primary; tumor growth; cytokeratin 14; metastatic breast cancer; hypoxia inducible factor 1alpha; oxygen consumption; cd24 antigen; transcription factor twist; glycolysis; oxidative phosphorylation; oxidation reduction reaction; oxidation-reduction; notch1 receptor; metabolic regulation; glucose transporter 1; kruppel like factor 4; cytokeratin 18; cytokeratin 8; vimentin; epithelial-mesenchymal transition; mammary neoplasms, animal; epithelial mesenchymal transition; calvasculin; osteonectin; calcyclin; cell plasticity; cytokeratin 17; gain of function mutation; metabolic reprogramming; guide rna; gene knockdown; humans; human; female; article; claudin 3; claudin 7; differential expression analysis; glutathione peroxidase 2; twist related protein 1; redox signaling; single cell rna seq; experimental mammary neoplasm; second primary neoplasm; aldh2 protein; arc protein; col18a1 protein; collagen type i alpha 1 chain; mest protein; protein jagged 1; breast tumor cell line |
| Journal Title: | British Journal of Cancer |
| Volume: | 130 |
| Issue: | 6 |
| ISSN: | 0007-0920 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-04-06 |
| Start Page: | 908 |
| End Page: | 924 |
| Language: | English |
| DOI: | 10.1038/s41416-023-02522-5 |
| PUBMED: | 38238426 |
| PROVIDER: | scopus |
| PMCID: | PMC10951347 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
