1. TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma.
- Author
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Oshimori N, Oristian D, and Fuchs E
- Subjects
- 9,10-Dimethyl-1,2-benzanthracene, Animals, Carcinoma, Squamous Cell drug therapy, Cisplatin therapeutic use, Female, Gene Expression Profiling, Glutathione metabolism, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms metabolism, Heterografts, Humans, Mice, Mice, Nude, NF-E2-Related Factor 2, Neoplasm Transplantation, Neoplastic Stem Cells metabolism, Skin Neoplasms drug therapy, Tetradecanoylphorbol Acetate, Carcinoma, Squamous Cell metabolism, Drug Resistance, Neoplasm, Signal Transduction, Skin Neoplasms metabolism, Transforming Growth Factor beta metabolism
- Abstract
Subsets of long-lived, tumor-initiating stem cells often escape cancer therapies. However, sources and mechanisms that generate tumor heterogeneity and drug-resistant cell population are still unfolding. Here, we devise a functional reporter system to lineage trace and/or genetic ablate signaling in TGF-β-activated squamous cell carcinoma stem cells (SCC-SCs). Dissecting TGF-β's impact on malignant progression, we demonstrate that TGF-β concentrating near tumor-vasculature generates heterogeneity in TGF-β signaling at tumor-stroma interface and bestows slower-cycling properties to neighboring SCC-SCs. While non-responding progenies proliferate faster and accelerate tumor growth, TGF-β-responding progenies invade, aberrantly differentiate, and affect gene expression. Intriguingly, TGF-β-responding SCC-SCs show increased protection against anti-cancer drugs, but slower-cycling alone does not confer survival. Rather, TGF-β transcriptionally activates p21, which stabilizes NRF2, thereby markedly enhancing glutathione metabolism and diminishing effectiveness of anti-cancer therapeutics. Together, these findings establish a surprising non-genetic paradigm for TGF-β signaling in fueling heterogeneity in SCC-SCs, tumor characteristics, and drug resistance., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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