Tumor Initiation Capacity and Therapy Resistance Are Differential Features of EMT-Related Subpopulations in the NSCLC Cell Line A549.

Details

Serval ID
serval:BIB_0AD21239D867
Type
Article: article from journal or magazin.
Collection
Publications
Title
Tumor Initiation Capacity and Therapy Resistance Are Differential Features of EMT-Related Subpopulations in the NSCLC Cell Line A549.
Journal
Neoplasia
Author(s)
Tièche C.C., Gao Y., Bührer E.D., Hobi N., Berezowska S.A., Wyler K., Froment L., Weis S., Peng R.W., Bruggmann R., Schär P., Amrein M.A., Hall SRR, Dorn P., Kocher G., Riether C., Ochsenbein A., Schmid R.A., Marti T.M.
ISSN
1476-5586 (Electronic)
ISSN-L
1476-5586
Publication state
Published
Issued date
02/2019
Peer-reviewed
Oui
Volume
21
Number
2
Pages
185-196
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Cell lines are essential tools to standardize and compare experimental findings in basic and translational cancer research. The current dogma states that cancer stem cells feature an increased tumor initiation capacity and are also chemoresistant. Here, we identified and comprehensively characterized three morphologically distinct cellular subtypes in the non-small cell lung cancer cell line A549 and challenge the current cancer stem cell dogma. Subtype-specific cellular morphology is maintained during short-term culturing, resulting in the formation of holoclonal, meroclonal, and paraclonal colonies. A549 holoclone cells were characterized by an epithelial and stem-like phenotype, paraclone cells featured a mesenchymal phenotype, whereas meroclone cells were phenotypically intermediate. Cell-surface marker expression of subpopulations changed over time, indicating an active epithelial-to-mesenchymal transition (EMT), in vitro and in vivo. EMT has been associated with the overexpression of the immunomodulators PD-L1 and PD-L2, which were 37- and 235-fold overexpressed in para- versus holoclone cells, respectively. We found that DNA methylation is involved in epigenetic regulation of marker expression. Holoclone cells were extremely sensitive to cisplatin and radiotherapy in vitro, whereas paraclone cells were highly resistant. However, inhibition of the receptor tyrosine kinase AXL, whose expression is associated with an EMT, specifically targeted the otherwise highly resistant paraclone cells. Xenograft tumor formation capacity was 24- and 269-fold higher in holo- than mero- and paraclone cells, respectively. Our results show that A549 subpopulations might serve as a unique system to explore the network of stemness, cellular plasticity, tumor initiation capacity, invasive and metastatic potential, and chemo/radiotherapy resistance.
Keywords
A549 Cells, Animals, Biomarkers, Carcinoma, Non-Small-Cell Lung/genetics, Carcinoma, Non-Small-Cell Lung/metabolism, Carcinoma, Non-Small-Cell Lung/pathology, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic/genetics, DNA Damage, DNA Methylation, Disease Models, Animal, Epithelial-Mesenchymal Transition/genetics, Gene Expression Profiling, Humans, Immunophenotyping, Lung Neoplasms/genetics, Lung Neoplasms/metabolism, Lung Neoplasms/pathology, Mice, Neoplastic Stem Cells/metabolism, Neoplastic Stem Cells/pathology, Transcriptome
Pubmed
Web of science
Open Access
Yes
Create date
29/06/2020 9:30
Last modification date
30/06/2020 5:26
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