Ren, Zuen, Liang, Huizhi, Dharmaratne, Malindrie, Morales-Gallego, Miriam, Fard, Atefeh Taherian, Mar, Jessica, Suyama, Kimita, Benard, Outhiriaradjou, Prystowsky, Michael B, Norton, Larry, Hazan, Rachel B (2022) Loss of glutathione peroxidase 2 promotes epithelial to mesenchymal transition and breast cancer metastasis. In: American Association for Cancer Research Annual Meeting 2022, 2022 Apr 8-13, Philadelphia, PA.
Abstract
The processes regulating tumor metastasis are multivariate and complex. Redox regulation of the tumor phenotype by GPx2 knockdown (KD) in breast cancer led us to uncover dramatic effects on spontaneous metastasis. Analysis of single cell RNA sequencing (scRNAseq) data from GPx2 KD tumor and control tumor, revealed that both tumors were comprised of several luminal-like tumor cell clusters and one mesenchymal-like cell cluster (cluster 3). Notably, GPx2 KD promoted a significant increase in the size of mesenchymal cells (cluster 3) relative to control, which might be due to the stimulation of epithelial-to-mesenchymal transition (EMT) in response to GPx2 loss. In support of this view, GPx2 KD stimulated an increase in mRNA expression of basal/mesenchymal (KRT5, KRT14, KRT17, Vimentin, Twist1, Twist2, CDH2) genes and a decrease in mRNA expression of epithelial/luminal (Cldn7 and Epcam) genes, especially in cluster 3. Moreover, GPx2 KD upregulated mRNA expression of basal/mesenchymal (Twist2, CDH2, and KRT14) genes in most luminal-like clusters expressing epithelial/luminal (Epcam, Cldn3/7, CDH1, KRT8/18) genes, implying these clusters may be undergoing EMT transition in a hybrid epithelial/mesenchymal state in response to GPx2 loss. Validation of these data in cell lines and tumors showed that GPx2 KD dramatically enhanced EMT via activation of ROS/HIF1α-mediated signaling. Importantly, these effects were reversed by GPx2 re-expression or HIF1α inhibition, which was capable of suppressing EMT and metastasis. Collectively, these results indicate that GPx2 loss promotes breast cancer metastasis by stimulating EMT due to HIF1α signaling, highlighting the impact of GPx2 and HIF1 on therapeutic intervention in metastasis.
| Item Type: | Conference or Workshop Item (Poster) |
|---|---|
| Subjects: | diseases & disorders > cancer > cancer types > breast cancer diseases & disorders > cancer > metastasis |
| CSHL Authors: | |
| Communities: | CSHL labs > Wigler lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 2022 |
| Date Deposited: | 11 Oct 2023 15:40 |
| Last Modified: | 11 Oct 2023 15:40 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41188 |
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