Lung cancer stem cells and their aggressive progeny, controlled by EGFR/MIG6 inverse expression, dictate a novel NSCLC treatment approach
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Zhiguang Xiao1,2, Bianca Sperl1, Silvia Gärtner1, Tatiana Nedelko3, Elvira Stacher-Priehse4, Axel Ullrich1 and Pjotr G. Knyazev1,5
1Department of Molecular Biology, Max-Planck Institute of Biochemistry, Martinsried, Munich, 82152, Germany
2Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
3Department of Medicine III, Klinikum rechts der Isar, TUM, Munich, 81675, Germany
4Asclepius Institute of Pathology, Gauting, 82131, Germany
5Current address: DoNatur GmbH, Martinsried, Munich, 82152, Germany
Pjotr G. Knyazev, email: [email protected]
Zhiguang Xiao, email: [email protected]
Keywords: NSCLC; cancer stem cells; niches; EGFR/MIG6; drug resistance
Received: January 29, 2019 Accepted: March 04, 2019 Published: April 02, 2019
The lung cancer stem cell (LuCSC) model comprises an attractive framework to explore acquired drug resistance in non-small cell lung cancer (NSCLC) treatment. Here, we used NSCLC cell line model to translate cellular heterogeneity into tractable populations to understand the origin of lung cancers and drug resistance. The epithelial LuCSCs, presumably arising from alveolar bipotent stem/progenitor cells, were lineage naïve, noninvasive, and prone to creating aggressive progeny expressing AT2/AT1 markers. LuCSC-holoclones were able to initiate rimmed niches, where their specialization created pseudo-alveoli structures. Mechanistically, LuCSC transitioning from self-renewal (β-catenin and Nanog signaling) to malignant lineage differentiation is regulated by EGFR activation and the inverse inhibition of tumor suppressor MIG6. We further identified the functional roles of endogenous EGFR signaling in mediating progeny invasiveness and their ligands in LuCSC differentiation. Importantly, drug screening demonstrated that EGFR driving progeny were strongly responsive to TKIs; however, the LuCSCs were exclusively resistant but sensitive to AMPK agonist Metformin, antibiotic Salinomycin and to a lesser degree Carboplatin. Our data reveals previously an unknown mechanism of NSCLC resistance to EGFR-TKIs, which is associated with LuCSCs bearing a silenced EGFR and inversely expressed MIG6 suppressor gene. Taken altogether, successful NSCLC treatment requires development of a novel combination of drugs, efficiently targeting both LuCSCs and heterogeneous progeny.
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