Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer.

In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression.

Redox signalling regulates breast cancer metastasis via phenotypic and metabolic reprogramming due to p63 activation by HIF1α.

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.

p21CIP1 Promotes Mammary Cancer-Initiating Cells via Activation of Wnt/TCF1/CyclinD1 Signaling.

Cancer stem cells (CSC) generate and sustain tumors due to tumor-initiating potential, resulting in recurrence or metastasis. We showed that knockout of the cell-cycle inhibitor, p21CIP1, in the PyMT mammary tumor model inhibits metastasis; however the mechanism remained unknown. Here, we show a pivotal role for p21 in potentiating a cancer stem-like phenotype. p21 knockout in PyMT mammary tumor cells caused dramatic suppression of CSC properties involving tumorsphere formation, ALDH1 activity, and tumor-initiating potential, which were in turn rescued by p21 overexpression into PyMT/p21 knockout cells. Interestingly, p21 knockout dramatically suppresses Wnt/ß-catenin signaling activity, leading to striking inhibition of LEF1 and TCF1 expression. TCF1 knockdown in PyMT cells suppressed tumorsphere formation due to Cyclin D1 attenuation. These data demonstrate that p21 promotes a CSC-like phenotype via activation of Wnt/TCF1/Cyclin D1 signaling. IMPLICATIONS: p21 is a strong promoter of mammary CSCs.

Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is especially beneficial to patients with exon 19 deletion compared with exon 21 L858R mutation in non-small-cell lung cancer: Systematic review and meta analysis.

BACKGROUND: The correlation between epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and EGFR sensitive mutation subtypes in advanced or metastatic non-small cell lung cancer (NSCLC) remains uncertain. We performed this meta-analysis to determine different clinical outcomes between patients with exon 19 deletion accepting EGFR-TKI therapy compared with those with exon 21 L858R mutation. METHODS: PubMed and Web of Science were analyzed for eligible trials. Raw data were extracted to give pooled estimates of the effect of EGFR-TKI therapy on objective response rate (ORR), one-year progression-free survival (PFS), and two-year overall survival (OS). RESULTS: We identified 13 eligible trials involving 912 patients. Prospective meta-analysis demonstrated that the ORR of the 19 deletion group was significantly higher than the 21 L858R mutation group (odds ratio [OR] 1.98, 95% confidence interval [CI] 1.18-3.33; P = 0.01), but no statistical significance between the one-year PFS rate of the 19 deletion and 21 L858R groups (OR 1.44, 95% CI 0.96-2.18; P = 0.08) was found. However, retrospective meta-analysis demonstrated that a significantly higher one-year PFS rate was associated with the 19 deletion group (OR 1.73, 95% CI 1.17-2.56; P = 0.006). The two-year survival rate of the 19 deletion group was significantly higher than the 21 L858R group (OR 5.27, 95 % CI 1.76-15.71; P = 0.003). CONCLUSIONS: In advanced NSCLC patients, an exon 19 deleton may provide superior ORR, PFS, and OS after EGFR-TKI treatment compared with an exon 21 L858R mutation.

Randomized controlled trials of induction treatment and surgery versus combined chemotherapy and radiotherapy in stages IIIA-N2 NSCLC: a systematic review and meta-analysis.

BACKGROUND: The efficacy of induction treatment plus surgery for improving postoperative survival in patients with non-small-cell lung cancer (NSCLC) in stages IIIA-N2 is controversial, especially compared with the combined chemotherapy and radiotherapy. We therefore performed a systematic review and meta-analysis of the published phase III randomized clinical trials (RCTs) to quantitatively evaluate the survival benefit of preoperative induction treatment vs. combined chemoradiotherapy. METHODS: We systematically searched for trials that started after January, 1980. We excluded relevant studies using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) standards. Our primary endpoint, overall survival (OS), was defined as the time from randomisation until death (any cause). Secondary endpoint was progression free survival (PFS). PubMed, EMBASE and Cochrane library were used for the study search. All analyses were by intention to treat. RESULTS: Three studies (1,084 patients) were centrally selected and analyzed for the present meta-analysis. Combination of the three randomized controlled trials showed that there was no significant benefit of induction treatment plus surgery compared to combined chemoradiotherapy on 2-year OS [risk ratio (RR) =1.00; 95% CI, 0.85-1.17; P=0.98] and 4-year OS (RR =1.13; 95% CI, 0.85-1.51; P=0.39). However, from the subgroup analysis, it showed a significant PFS benefit (RR =1.78; 95% CI, 1.08-2.92; P=0.02) regarded chemoradiotherapy as preoperative induction treatment, compared with chemotherapy alone for induction treatment (PFS) (RR =1.05; 95% CI, 0.61-1.81; P=0.86). CONCLUSIONS: There was no significant OS benefit of induction treatment plus surgery compared with combined chemoradiotherapy in patients with NSCLC (stages IIIA-pN2) at 2 and 4 years. However, we could conclude PFS could be improved when radiation therapy was added into preoperative induction treatment. Given the potential advantages of adding radiation preoperatively, clinicians should consider using this treatment strategy in the stage IIIA-N2 disease after fully assessment of the patients.