Theranostics 2022; 12(16):7051-7066. doi:10.7150/thno.73099 This issue Cite

Research Paper

ERK inactivation enhances stemness of NSCLC cells via promoting Slug-mediated epithelial-to-mesenchymal transition

Shurui Cai1,2*, Na Li1,2*, Xuetao Bai1,2, Lu Liu1,2, Ananya Banerjee1,2, Kousalya Lavudi1,2, Xiaoli Zhang3, Jihe Zhao4, Monica Venere1,2, Wenrui Duan5, Junran Zhang1,2, Meng X. Welliver1,2, Kai He6, Qi-En Wang1,2✉

1. Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
2. Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
3. Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
4. Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA.
5. Department of Human & Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA.
6. Department of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
*Authors contribute equally to this work.

Citation:
Cai S, Li N, Bai X, Liu L, Banerjee A, Lavudi K, Zhang X, Zhao J, Venere M, Duan W, Zhang J, Welliver MX, He K, Wang QE. ERK inactivation enhances stemness of NSCLC cells via promoting Slug-mediated epithelial-to-mesenchymal transition. Theranostics 2022; 12(16):7051-7066. doi:10.7150/thno.73099. https://www.thno.org/v12p7051.htm
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Abstract

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Rationale: The mitogen-activated protein kinase pathway (MAPK) is one of the major cancer-driving pathways found in non-small cell lung cancer (NSCLC) patients. ERK inhibitors (ERKi) have been shown to be effective in NSCLC patients with MAPK pathway mutations. However, like other MAPK inhibitors, ERKi rarely confers complete and durable responses. The mechanism of tumor relapse after ERKi treatment is yet defined.

Methods: To best study the mechanism of tumor relapse after ERK inhibitor treatment in NSCLC patients, we treated various NSCLC cell lines and patient-derived xenograft (PDX) with ERK inhibitors and evaluated the enrichment of cancer stem cell (CSC) population. We then performed a Next-generation sequencing (NGS) to identify potential pathways that are responsible for the CSC enrichment. Further, the involvement of specific pathways was examined using molecular and cellular methods. Finally, we investigated the therapeutic benefits of ERKi treatment combined with JAK/STAT pathway inhibitor using cellular and xenograft NSCLC models.

Results: We found that ERKi treatment expands the CSC population in NSCLC cells through enhanced epithelial-to-mesenchymal transition (EMT)-mediated cancer cell dedifferentiation. Mechanistically, ERK inactivation induces EMT via pSTAT3-mediated upregulation of Slug, in which, upregulation of miR-204 and downregulation of SPDEF, a transcription repressor of Slug, are involved. Finally, the JAK/STAT pathway inhibitor Ruxolitinib blocks the ERK inactivation-induced EMT and CSC expansion, as well as the tumor progression in xenograft models after ERKi treatment.

Conclusions: This study revealed a potential tumor relapse mechanism of NSCLC after ERK inhibition through the unintended activation of the EMT program, ascertained the pSTAT-miR-204-SPDEF-Slug axis, and provided a promising combination inhibitor approach to prevent tumor relapse in patients.

Keywords: ERK, ERK inhibitor, Non-small cell lung cancer, Epithelial-to-mesenchymal transition, Slug, Cancer stem cell, dedifferentiation


Citation styles

APA
Cai, S., Li, N., Bai, X., Liu, L., Banerjee, A., Lavudi, K., Zhang, X., Zhao, J., Venere, M., Duan, W., Zhang, J., Welliver, M.X., He, K., Wang, Q.E. (2022). ERK inactivation enhances stemness of NSCLC cells via promoting Slug-mediated epithelial-to-mesenchymal transition. Theranostics, 12(16), 7051-7066. https://doi.org/10.7150/thno.73099.

ACS
Cai, S.; Li, N.; Bai, X.; Liu, L.; Banerjee, A.; Lavudi, K.; Zhang, X.; Zhao, J.; Venere, M.; Duan, W.; Zhang, J.; Welliver, M.X.; He, K.; Wang, Q.E. ERK inactivation enhances stemness of NSCLC cells via promoting Slug-mediated epithelial-to-mesenchymal transition. Theranostics 2022, 12 (16), 7051-7066. DOI: 10.7150/thno.73099.

NLM
Cai S, Li N, Bai X, Liu L, Banerjee A, Lavudi K, Zhang X, Zhao J, Venere M, Duan W, Zhang J, Welliver MX, He K, Wang QE. ERK inactivation enhances stemness of NSCLC cells via promoting Slug-mediated epithelial-to-mesenchymal transition. Theranostics 2022; 12(16):7051-7066. doi:10.7150/thno.73099. https://www.thno.org/v12p7051.htm

CSE
Cai S, Li N, Bai X, Liu L, Banerjee A, Lavudi K, Zhang X, Zhao J, Venere M, Duan W, Zhang J, Welliver MX, He K, Wang QE. 2022. ERK inactivation enhances stemness of NSCLC cells via promoting Slug-mediated epithelial-to-mesenchymal transition. Theranostics. 12(16):7051-7066.

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