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Cell. 2015 Feb 26;160(5):963-976. doi: 10.1016/j.cell.2015.01.043.

TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma.

Author information

1
Robin Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
2
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.

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.

PMID:
25723170
PMCID:
PMC4509607
DOI:
10.1016/j.cell.2015.01.043
[Indexed for MEDLINE]
Free PMC Article

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