[PDF][PDF] TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma

N Oshimori, D Oristian, E Fuchs - Cell, 2015 - cell.com
N Oshimori, D Oristian, E Fuchs
Cell, 2015cell.com
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 …
Summary
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.
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