Nutritional stress reprograms dedifferention in glioblastoma multiforme driven by PTEN/Wnt/Hedgehog axis: a stochastic model of cancer stem cells.

The emergence and maintenance of cancer stem-like cells (CSCs) are usually governed by tumor niche. Tumor niche always provides metabolic challenges to cancer cells and CSCs mostly because of tissue hypoxia. However, the role of micro-environmental nutritional stress (NS) in dedifferentiation of cancer cells is poorly defined. Here, we developed a stochastic model of CSCs by gradual nutritional deprivation in glioblastoma multiforme (GBM) cells used as a model system. Nutritional deprivation induced enhanced expression of glioblastoma stem-like cells (GSCs)-specific biomarkers with higher invasive and angiogenic properties. This NS-induced cells showed higher xenobiotic efflux ability, and hence exhibit resistance to multiple anticancer drugs. In the molecular level, such NS activated Wnt and Hedgehog (Hh) signaling pathways by stabilizing β-catenin and Gli1, respectively, through modulation of GSK3β/AKT axis. GBM-specific PTEN (phosphatase and tensin homolog) mutation contributed to better phenoconversion toward GSCs. Knocking down of PTEN coupled with NS induction enhanced neurosphere formation, GSC-specific biomarker expressions, and activation of Wnt/Hh signaling. Thus, such an in-depth understanding of dedifferentiation of GBM cells to GSCs under NS suggested that targeting Wnt/Hh signaling possibly be a better therapeutic approach.