Discovery and characterization of plastic subpopulations associated with distinct hallmarks of cancer in the NSCLC cell line A549

Tièche, Colin Charles; Schmid, Ralph A. (2017). Discovery and characterization of plastic subpopulations associated with distinct hallmarks of cancer in the NSCLC cell line A549. (Dissertation, Graduate School for Cellular and Biomedical Sciences)

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Lung cancer is the leading cause of cancer-related mortality worldwide and is responsible
for more than 1 million deaths each year. Despite enormous efforts put in the development of
novel treatment strategies, the 5-year survival rate for patients diagnosed with non-small cell
lung cancer (NSCLC) remains very low. This is partly due to the difficulty in detecting the
disease at early an therefore better treatable time points, which leads to the diagnosis of already
locally advanced NSCLC in one-third of the patients. For these patients, concurrent chemo-
and/or radiotherapy are considered as standard therapies. The other cause leading to poor
survival rate is proposed to lay within the potential of certain tumor cells to resist common
treatment strategies and to promote tumor re-initiation, resulting in disease relapse. Up to
date, these particular tumor cells have accumulated a variety of characteristic denominations,
such as tumor-initiating and tumor-propagating cells, chemoresistant and therefore also tumor-
reinitiating cells, as well as metastasizing cells. The most widely used term, which combines all
these attributes and features, is cancer stem cell (CSC).
Within the first 2 years of my PhD we focused on commonly used treatment strategies for
NSCLC and attempted to optimize the gold standard therapy, consisting of pemetrexed and
cisplatin, recently recommended for adenocarcinoma lung cancer patients. We demonstrated
that the anti-cancer effect of the combination chemotherapy could be enhanced in a schedule-
dependent manner. Compared to the simultaneous exposure, called concurrent therapy in the
clinic, the pretreatment with pemetrexed prior to cisplatin, i.e. sequential treatment, improved
the combination therapy’s efficiency in vitro and provides evidence for the adaptation of the
treatment strategy in clinical settings. The follow up project consisted in extrapolating the
observed findings to chemo-radiotherapy. Indeed, the pretreatment with pemetrexed prior to
ionizing radiation, also optimized the anticancer treatment modality.
The second project was initiated after the detection of phenotypically distinct cell and co-
lony morphologies within the adenocarcinoma cell line A549 used in the treatment optimization
studies. We established relatively stable cultures of three distinct subpopulations, termed holo-,
mero- and paraclonal, starting with the isolation of single colonies from the parental popula-
tion. We were able to specifically connect phenotype with differential expression profiles and
to further attribute distinct hall marks of cancer, i.e. stemness, tumor initiation, treatment
resistance, migration/invasion, to the different subpopulations. Holoclone cells are characteri-
zed by an epithelial and stem-like phenotype and feature highest tumor-initiation potential.
In contrast, paraclone cells exhibit a mesenchymal phenotype, resulting from the activation
of epithelial-mesenchymal transition, possess migration and invasion potential and are more tolerant to chemo and IR treatment. Meroclone cells feature intermediate phenotype and gene
expression signature. We further demonstrate high degree of plasticity among the phenotypes.
In summary, we demonstrate that the cell line A549 consists of subpopulations of cells residing
in distinct but dynamic phenotypic states, to which functional properties can be attributed.
The model might allow the study of non-genetically dictated processes, such as the epithelial-
mesenchymal transition and dedifferentiation, and could evoke a potential adaptation of the
classical CSC theory.

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