Abstract 963: Targeting epithelial-mesenchymal plasticity via ribosome biogenesis inhibition reduces chemoresistant metastasis of breast cancer

Abstract Epithelial to mesenchymal transition (EMT) plays an important role in metastasis and chemoresistance. However, targeting EMT has been challenging due to the complex and redundant EMT signaling pathways. Moreover, EMT inhibition would unequivocally promote its reversed process, mesenchymal to epithelial transition (MET), which also favors malignancy progression. To solve this EMT targeting paradox, we proposed to target the ability of tumor cells to oscillate between epithelial and mesenchymal states, the epithelial to mesenchymal plasticity (EMP), which encompasses both EMT and MET. Using a SnailCre-ERT2 mediated EMT lineage-tracing model, we confirmed the involvement of EMP in chemoresistant metastasis of breast cancer. Single-cell transcriptome analyses of tumor cells in the transitioning phases of EMT or MET consistently revealed that ribosome biogenesis (RiBi) was specifically elevated regardless of their destined phenotypical fates. Further analyses delineated that the upregulation of RiBi and the subsequent nascent protein synthesis via the intensified ERK and mTOR signalings were vital for cancer cells to transit between epithelial and mesenchymal states. Importantly, inhibiting the excessive RiBi by either genetic or pharmacological means impaired EMP, as both EMT and MET processes were impeded, leading to significantly reduced metastatic outgrowth of chemoresistant tumor cells. Our studies revealed that elevated RiBi is required for tumor cells to “Ping Pong” between epithelial and mesenchymal states. Targeting the EMP via RiBi inhibition provides a feasible strategy to improve therapies for advanced breast cancers. Citation Format: Yi Ban, Wenjuan Dong, Yue Zou, Sharrell B. Lee, Jianting Sheng, Yuliang Cao, Stephen T.C. Wong, Dingcheng Gao. Targeting epithelial-mesenchymal plasticity via ribosome biogenesis inhibition reduces chemoresistant metastasis of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 963.