PMID- 38238426
OWN - NLM
STAT- MEDLINE
DCOM- 20240321
LR  - 20240322
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 130
IP  - 6
DP  - 2024 Apr
TI  - Redox signalling regulates breast cancer metastasis via phenotypic and metabolic 
      reprogramming due to p63 activation by HIF1alpha.
PG  - 908-924
LID - 10.1038/s41416-023-02522-5 [doi]
AB  - 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 HIF1alpha 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 HIF1alpha, underlying phenotypic and metabolic plasticity leading to mammary 
      tumour metastasis.
CI  - (c) 2024. The Author(s).
FAU - Ren, Zuen
AU  - Ren Z
AD  - Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, 
      USA.
AD  - Center for Cancer Research, Massachusetts General Hospital and Harvard Medical 
      School, Boston, MA, 02114, USA.
FAU - Dharmaratne, Malindrie
AU  - Dharmaratne M
AD  - Australian Institute for Bioengineering and Nanotechnology, University of 
      Queensland, Brisbane, QLD, Australia.
FAU - Liang, Huizhi
AU  - Liang H
AD  - Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, 
      USA.
FAU - Benard, Outhiriaradjou
AU  - Benard O
AD  - Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, 
      USA.
FAU - Morales-Gallego, Miriam
AU  - Morales-Gallego M
AD  - Francisco de Vitoria University, Madrid, Spain.
FAU - Suyama, Kimita
AU  - Suyama K
AD  - Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, 
      USA.
FAU - Kumar, Viney
AU  - Kumar V
AD  - Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, 
      USA.
FAU - Fard, Atefeh Taherian
AU  - Fard AT
AD  - Australian Institute for Bioengineering and Nanotechnology, University of 
      Queensland, Brisbane, QLD, Australia.
FAU - Kulkarni, Ameya S
AU  - Kulkarni AS
AD  - Department of Endocrinology, Albert Einstein College of Medicine, Bronx, NY, 
      10461, USA.
FAU - Prystowsky, Michael
AU  - Prystowsky M
AD  - Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, 
      USA.
FAU - Mar, Jessica C
AU  - Mar JC
AD  - Australian Institute for Bioengineering and Nanotechnology, University of 
      Queensland, Brisbane, QLD, Australia.
FAU - Norton, Larry
AU  - Norton L
AD  - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, 
      10021, USA.
FAU - Hazan, Rachel B
AU  - Hazan RB
AUID- ORCID: 0000-0002-1441-4584
AD  - Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, 
      USA. rachel.hazan@einsteinmed.edu.
LA  - eng
GR  - P01 CA257885/CA/NCI NIH HHS/United States
GR  - P30 CA013330/CA/NCI NIH HHS/United States
GR  - S10 OD026852/OD/NIH HHS/United States
PT  - Journal Article
DEP - 20240118
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
SB  - IM
MH  - Animals
MH  - Humans
MH  - Female
MH  - *Breast Neoplasms/genetics/pathology
MH  - Metabolic Reprogramming
MH  - Epithelial-Mesenchymal Transition/genetics
MH  - *Mammary Neoplasms, Animal
MH  - *Lung Neoplasms/genetics/secondary
MH  - *Neoplasms, Second Primary
MH  - Oxidation-Reduction
MH  - Cell Line, Tumor
MH  - Neoplasm Metastasis
PMC - PMC10951347
COIS- The authors declare no competing interests.
EDAT- 2024/01/19 00:42
MHDA- 2024/03/21 12:46
PMCR- 2024/01/18
CRDT- 2024/01/18 23:21
PHST- 2023/03/16 00:00 [received]
PHST- 2023/11/24 00:00 [accepted]
PHST- 2023/11/08 00:00 [revised]
PHST- 2024/03/21 12:46 [medline]
PHST- 2024/01/19 00:42 [pubmed]
PHST- 2024/01/18 23:21 [entrez]
PHST- 2024/01/18 00:00 [pmc-release]
AID - 10.1038/s41416-023-02522-5 [pii]
AID - 2522 [pii]
AID - 10.1038/s41416-023-02522-5 [doi]
PST - ppublish
SO  - Br J Cancer. 2024 Apr;130(6):908-924. doi: 10.1038/s41416-023-02522-5. Epub 2024 
      Jan 18.