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

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.

• Authors: 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
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 30 Issue 11 Pg. 3341-3357 (11 02 2022) ISSN: 1525-0024 [Electronic] United States
• PMID: 35733338 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• MDS1 and EVI1 Complex Locus Protein
• MECOM protein, human
• Transcription Factors

Topics

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