TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma.
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.
Robin Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Naoki
N
Oshimori
Robin Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Daniel
D
Oristian
Robin Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA; Howard Hughes Medical Institute, 1230 York Avenue, New York, NY 10065, USA. Electronic address: fuchslb@rockefeller.edu.
Elaine
E
Fuchs
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D005978:Glutathione / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016212:Transforming Growth Factor beta; D015127:9,10-Dimethyl-1,2-benzanthracene; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate; D002945:Cisplatin