Targeting ribosome biogenesis as a novel therapeutic approach to overcome EMT-related chemoresistance in breast cancer

Author:

Ban Yi12ORCID,Zou Yue12,Liu Yingzhuo12,Lee Sharrel123,Bednarczyk Robert B12,Sheng Jianting4,Cao Yuliang4,Wong Stephen TC456,Gao Dingcheng1237ORCID

Affiliation:

1. Department of Cardiothoracic Surgery, Weill Cornell Medicine

2. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine

3. Neuberger Berman Lung Cancer Center, Weill Cornell Medicine

4. Systems Medicine and Bioengineering Department, Houston Methodist Cancer Center, Houston Methodist Hospital

5. Department of Radiology, Houston Methodist Cancer Center, Houston Methodist Hospital

6. Department of Pathology and Laboratory Medicine, Houston Methodist Cancer Center, Houston Methodist Hospital

7. Department of Cell and Developmental Biology, Weill Cornell Medicine

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.

Funder

National Cancer Institute

Publisher

eLife Sciences Publications, Ltd

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