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

Tièche, Colin; Gao, Yanyun; Bührer, Elias; Hobi, Nina; Berezowska, Sabina Anna; Wyler, Kurt; Froment, Laurène; Weis, Stefan; Peng, Ren-Wang; Bruggmann, Rémy; Schär, Primo; Amrein, Michael Alex; Hall, Sean; Dorn, Patrick; Kocher, Gregor; Riether, Carsten; Ochsenbein, Adrian; Schmid, Ralph; Marti, Thomas (2019). Tumor Initiation Capacity and Therapy Resistance Are Differential Features of EMT-Related Subpopulations in the NSCLC Cell Line A549. Neoplasia, 21(2), pp. 185-196. Elsevier 10.1016/j.neo.2018.09.008

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Central Animal Facility
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Core Facility Zytometrie-Labor/FACSlab
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
09 Interdisciplinary Units > Microscopy Imaging Center MIC
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Genomics

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Tièche, Colin; Gao, Yanyun; Bührer, Elias; Berezowska, Sabina Anna; Wyler, Kurt; Peng, Ren-Wang; Bruggmann, Rémy; Amrein, Michael Alex; Hall, Sean; Dorn, Patrick; Kocher, Gregor; Riether, Carsten; Ochsenbein, Adrian; Schmid, Ralph and Marti, Thomas

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

1476-5586

Publisher:

Elsevier

Language:

English

Submitter:

Sabina Anna Berezowska

Date Deposited:

21 Feb 2019 13:29

Last Modified:

21 Feb 2019 13:29

Publisher DOI:

10.1016/j.neo.2018.09.008

PubMed ID:

30591423

BORIS DOI:

10.7892/boris.123431

URI:

https://boris.unibe.ch/id/eprint/123431

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