Lung cancer stem cells and their aggressive progeny, controlled by EGFR/MIG6 inverse expression, dictate a novel NSCLC treatment approach

Abstract

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.

In vivo and in vitro cell based model of lung adenocarcinoma from patients with pleural effusion

“…This staining pattern is in line with adenocarcinoma markers detected in tumor xenografts and indicate that both sublines are LAC cells. LAC is frequently associated with development of malignant PE, which occurs during disease progression [35]. The process of cancer progression is also accompanied by increased mutations in driver genes of LAC and likely contribute to CSC heterogeneity within tumor cells [24,35].…”

“…LAC is frequently associated with development of malignant PE, which occurs during disease progression [35]. The process of cancer progression is also accompanied by increased mutations in driver genes of LAC and likely contribute to CSC heterogeneity within tumor cells [24,35]. LAC cells in PE represent cell population released from tumor tissues via mechanism of epithelial-mesenchymal transition (EMT) characterized with down regulated cell-to-cell adhesion [34,43].…”

Transcription factor YY1 enhances the stemness of lung cancer cells by stabilizing hypoxia factor HIF‐1α under a hypoxic microenvironment

“…A large number of studies have confirmed that CSC also exists in lung cancer, and CSCs are considered to be the main cause of tumor recurrence and metastasis. 4 Yin-Yang 1 (YY1) is a member of GLI Kruppel family of zinc finger transcription factors and overexpressed in a variety of human cancer tissues, such as breast, colon, stomach, and prostate cancer. [5][6][7] Luo et al found that YY1 was highly expressed in esophageal cancer tissue, which was related to lymph node metastasis and clinical stage, and the prognosis of patients with YY1 high expression was poor, indicating that YY1 was closely related to the progress of esophageal cancer.…”

Itraconazole Alters the Stem Cell Characteristics of A549 and NCI-H460 Human Lung Cancer Cells by Suppressing Wnt Signaling

“…Lung cancer stem cells (CSCs) are a cell subset with properties of persistence or immortalization, self-renewal, and the potential to differentiate phenotypically in lung cancer or supporting tissues [4]. Lung CSCs may be involved in the occurrence and development of lung cancer and can provide novel therapeutic targets for treatment [4].…”

“…Lung cancer stem cells (CSCs) are a cell subset with properties of persistence or immortalization, self-renewal, and the potential to differentiate phenotypically in lung cancer or supporting tissues [4]. Lung CSCs may be involved in the occurrence and development of lung cancer and can provide novel therapeutic targets for treatment [4]. For example, Wu et al recently showed that depletion of the oncogene, prostate tumor overexpressed gene 1 (PTOV1), sensitized lung cancer cells to chemotherapy by reducing lung CSC-like traits [5].…”