Genome-Wide and Phenotypic Evaluation of Stem Cell Progenitors Derived From -Deficient Murine Lung Adenocarcinoma With Somatic Mutations.

Authors:
Maya Hassane
Maya Hassane
American University of Beirut
Hisham F Bahmad
Hisham F Bahmad
American University of Beirut
Ansam Sinjab
Ansam Sinjab
German Cancer Research Center
Junya Fujimoto
Junya Fujimoto
The University of Texas MD Anderson Cancer Center
United States
Humam Kadara
Humam Kadara
The University of Texas MD Anderson Cancer Center
Houston | United States

Front Oncol 2019 2;9:207. Epub 2019 Apr 2.

Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.

Lung adenocarcinomas (LUADs) with somatic mutations in the oncogene comprise the most common molecular subtype of lung cancer in smokers and present with overall dismal prognosis and resistance to most therapies. Our group recently demonstrated that tobacco carcinogen-exposed mice with knockout of the airway lineage G-protein coupled receptor, , develop LUADs with somatic mutations in . Earlier work has suggested that cancer stem cells (CSCs) play crucial roles in clonal evolution of tumors and in therapy resistance. To date, our understanding of CSCs in LUADs with somatic mutations remains lagging. Here we derived CSCs (as spheres in 3D cultures) with self-renewal properties from a murine -mutant LUAD cell line we previously established from a tobacco carcinogen-exposed mouse. Using syngeneic models, we found that these CSCs, compared to their parental isoforms, exhibited increased tumorigenic potential , particularly in female animals. Using whole-transcriptome sequencing coupled with pathways analysis and confirmatory PCR, we identified gene features ( = 2,600) differentially expressed in the CSCs compared to parental cells and that were enriched with functional modules associated with an augmented malignant phenotype including stemness, tumor-promoting inflammation and anti-oxidant responses. Further, based on predicted activation of GSK3β in CSCs, we found that tideglusib, an irreversible inhibitor of the kinase, exhibited marked anti-growth effects in the cultured CSCs. Our study underscores molecular cues in the pathogenesis of -mutant LUAD and presents new models to study the evolution, and thus high-potential targets, of this aggressive malignancy.

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Source
http://dx.doi.org/10.3389/fonc.2019.00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454871PMC
April 2019

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