TGF-β Promotes Heterogeneity and Drug Resistance in Squamous Cell Carcinoma

Naoki Oshimori, Daniel Oristian, Elaine Fuchs

Research output: Contribution to journalArticle

165 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)963-976
Number of pages14
JournalCell
Volume160
Issue number5
DOIs
StatePublished - Feb 26 2015
Externally publishedYes

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Drug Resistance
Tumors
Squamous Cell Carcinoma
Stem cells
Neoplastic Stem Cells
Pharmaceutical Preparations
Neoplasms
Stem Cells
Fueling
Metabolism
Gene expression
Glutathione
Epithelial Cells
Cells
Gene Expression
Therapeutics
Growth
Population

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

TGF-β Promotes Heterogeneity and Drug Resistance in Squamous Cell Carcinoma. / Oshimori, Naoki; Oristian, Daniel; Fuchs, Elaine.

In: Cell, Vol. 160, No. 5, 26.02.2015, p. 963-976.

Research output: Contribution to journalArticle

Oshimori, Naoki ; Oristian, Daniel ; Fuchs, Elaine. / TGF-β Promotes Heterogeneity and Drug Resistance in Squamous Cell Carcinoma. In: Cell. 2015 ; Vol. 160, No. 5. pp. 963-976.
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