TGF-ß promotes heterogeneity and drug resistance in squamous cell carcinoma.
Cell
; 160(5): 963-976, 2015 Feb 26.
Article
em En
| MEDLINE
| ID: mdl-25723170
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-ß-activated squamous cell carcinoma stem cells (SCC-SCs). Dissecting TGF-ß's impact on malignant progression, we demonstrate that TGF-ß concentrating near tumor-vasculature generates heterogeneity in TGF-ß 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-ß-responding progenies invade, aberrantly differentiate, and affect gene expression. Intriguingly, TGF-ß-responding SCC-SCs show increased protection against anti-cancer drugs, but slower-cycling alone does not confer survival. Rather, TGF-ß 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-ß signaling in fueling heterogeneity in SCC-SCs, tumor characteristics, and drug resistance.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Cutâneas
/
Carcinoma de Células Escamosas
/
Transdução de Sinais
/
Fator de Crescimento Transformador beta
/
Resistencia a Medicamentos Antineoplásicos
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article