Targeting Ribosome Biogenesis as a Novel Therapeutic Approach to Overcome EMT-related Chemoresistance in Breast Cancer

Yi Ban, Yue Zou, Sharrell B Lee, Robert B Bednarczyk, Jianting Sheng, Yuliang Cao, Stephen T C Wong, Dingcheng Gao

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Epithelial-to-mesenchymal transition (EMT) contributes significantly to chemotherapy resistance and remains a critical challenge in treating advanced breast cancer. The complexity of EMT, involving redundant pro-EMT signaling pathways and its paradox reversal process, mesenchymal-to-epithelial transition (MET), has hindered the development of effective treatments. In this study, we utilized a Tri-PyMT EMT lineage-tracing model in mice and single-cell RNA sequencing (scRNA-seq) to comprehensively analyze the EMT status of tumor cells. Our findings revealed elevated ribosome biogenesis (RiBi) during the transitioning phases of both EMT and MET processes. RiBi and its subsequent nascent protein synthesis mediated by ERK and mTOR signalings are essential for EMT/MET completion. Importantly, inhibiting excessive RiBi genetically or pharmacologically impaired the EMT/MET capability of tumor cells. Combining RiBi inhibition with chemotherapy drugs synergistically reduced metastatic outgrowth of epithelial and mesenchymal tumor cells under chemotherapies. Our study suggests that targeting the RiBi pathway presents a promising strategy for treating patients with advanced breast cancer.

Original languageEnglish (US)
JournaleLife
Volume12
DOIs
StatePublished - Sep 11 2024

Keywords

  • EMT
  • breast cancer
  • cancer biology
  • chemoresistance
  • human
  • mouse
  • ribosome biogenesis

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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