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

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-?-activated squamous cell carcinoma stem cells (SCC-SCs). Dissecting TGF-?'s impact on malignant progression, we demonstrate that TGF-? concentrating near tumor-vasculature generates heterogeneity in TGF-? 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-?-responding progenies invade, aberrantly differentiate, and affect gene expression. Intriguingly, TGF-?-responding SCC-SCs show increased protection against anti-cancer drugs, but slower-cycling alone does not confer survival. Rather, TGF-? 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-? signaling in fueling heterogeneity in SCC-SCs, tumor characteristics, and drug resistance.

SUBMITTER: Oshimori N 

PROVIDER: S-EPMC4509607 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature