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Molecular therapy : the journal of the American Society of Gene Therapy
11 02, 2022;30 (11): 3341-3357.

CRISPR-mediated MECOM depletion retards tumor growth by reducing cancer stem cell properties in lung squamous cell carcinoma.

Yuanyuan Ma, Bin Kang, Shaolei Li, Guoyun Xie, Jiwang Bi, Fuqiang Li, Guo An, Bing Liu, Jing Li, Yue Shen, Xun Xu, Huanming Yang, Yue Yang, Ying Gu, Nan Wu
Author Information
  1. Yuanyuan Ma: Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China.
  2. Bin Kang: BGI-Shenzhen, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Genome Read and Write, BGI-Shenzhen, Shenzhen 518120, China.
  3. Shaolei Li: Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China.
  4. Guoyun Xie: BGI-Shenzhen, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI-Shenzhen, Shenzhen 518120, China.
  5. Jiwang Bi: Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China.
  6. Fuqiang Li: BGI-Shenzhen, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI-Shenzhen, Shenzhen 518120, China.
  7. Guo An: Department of Laboratory Animals, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China.
  8. Bing Liu: Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China.
  9. Jing Li: BGI-Shenzhen, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Genome Read and Write, BGI-Shenzhen, Shenzhen 518120, China.
  10. Yue Shen: BGI-Shenzhen, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Genome Read and Write, BGI-Shenzhen, Shenzhen 518120, China.
  11. Xun Xu: BGI-Shenzhen, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Genome Read and Write, BGI-Shenzhen, Shenzhen 518120, China.
  12. Huanming Yang: BGI-Shenzhen, Shenzhen 518083, China; Guangdong Provincial Academician Workstation of BGI Synthetic Genomics, BGI-Shenzhen, Shenzhen 518120, China.
  13. Yue Yang: Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China. Electronic address: zlyangyue@bjmu.edu.cn.
  14. Ying Gu: BGI-Shenzhen, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Genome Read and Write, BGI-Shenzhen, Shenzhen 518120, China. Electronic address: guying@genomics.cn.
  15. Nan Wu: Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China. Electronic address: nanwu@bjmu.edu.cn.
PMID: 35733338 DOI: 10.1016/j.ymthe.2022.06.011

Abstract

Targeted therapy for lung squamous cell carcinoma (LUSC) remains a challenge due to the lack of robust targets. Here, we identified MECOM as a candidate of therapeutic target for LUSC by screening 38 genes that were commonly amplified in three pairs of primary tumors and patient-derived xenografts (PDXs) using a clustered regularly interspaced short palindromic repeats (CRISPR)-mediated approach. High MECOM expression levels were associated with poor prognosis. Forced expression of MECOM in LUSC cell lines promoted cancer stem cell (CSC) properties, and its knockout inhibited CSC phenotypes. Furthermore, systemic delivery of CRISPR-mediated MECOM depletion cassette using adenovirus with an adaptor, which is composed of a single-chain fragment variable (scFv) against epithelial cell adhesion molecules (EpCAM) fused to the ectodomain of coxsackievirus and adenovirus receptor, and a protector, which consists of the scFv connected to the hexon symmetry of the adenovirus, could specifically target subcutaneous and orthotopic LUSC and retard tumor growth. This study could provide a novel therapeutic strategy for LUSC with high efficacy and specificity.

Keywords

CRISPR MECOM cancer stem cells lung squamous cell carcinoma

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MeSH Term

Humans
Carcinoma, Non-Small-Cell Lung
Carcinoma, Squamous Cell
Cell Line, Tumor
Clustered Regularly Interspaced Short Palindromic Repeats
Gene Expression Regulation, Neoplastic
Lung Neoplasms
MDS1 and EVI1 Complex Locus Protein
Neoplastic Stem Cells
Transcription Factors
Animals

Chemicals

MDS1 and EVI1 Complex Locus Protein
MECOM protein, human
Transcription Factors
Journal Article Research Support, Non-U.S. Gov't

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