%0 Journal Article
%T Tumor Initiation Capacity and Therapy Resistance Are Differential Features of EMT-Related Subpopulations in the NSCLC Cell Line A549
%A Adrian Ochsenbein
%A Carsten Riether
%A Colin Charles Ti¨¨che
%A Elias Daniel B¨¹hrer
%A Gregor Kocher
%A Kurt Wyler
%A Laur¨¨ne Froment
%A Michael Alex Amrein
%A Nina Hobi
%A Patrick Dorn
%A Primo Sch£¿r
%A Ralph Alexander Schmid
%A Ren-Wang Peng
%A R¨¦my Bruggmann
%A Sabina Anna Berezowska
%A Sean Ralph Robert Hall
%A Stefan Weis
%A Thomas Michael Marti
%A Yanyun Gao
%J Archive of "Neoplasia (New York, N.Y.)".
%D 2019
%R 10.1016/j.neo.2018.09.008
%X 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¨Csmall 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
%K EMT
%K epithelial-to-mesenchymal transition
%K NSCLC
%K non¨Csmall cell lung cancers
%K CSCs
%K cancer stem cells
%K hybrid-E/M
%K hybrid epithelial/mesenchymal
%K GOseq
%K KEGG pathway enrichment analysis
%K MYC
%K cellular Myc
%K MYCN
%K N-Myc
%K POU5F1
%K OCT4
%K ALCAM
%K CD166
%K CDH1
%K E-cadherin
%K CDH17
%K Cadherin 17
%K VIM
%K Vimentin
%K SNAI1
%K SNAIL
%K SNAI2
%K SLUG
%K CTSB
%K Cathepsin B
%K MMP2
%K matrix metalloproteinase-2
%K SOX2+
%K high SOX2
%K CD90£¿
%K low CD90 expression
%K IR
%K ionizing radiation
%K EGFR
%K epidermal growth factor receptor
%K TIC
%K tumor initiation cell
%K SCLC
%K small cell lung cancer
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309124/