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TGF-β Promotes Heterogeneity and Drug Resistance in Squamous Cell Carcinoma
Open accessAbstract
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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“EMT also correlates with increased resistance of carcinoma cells to chemotherapies149–152.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [152]
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Metadata
- Authors
- Oshimori, N., Oristian, D., & Fuchs, E.
- Affiliations
- Rockefeller University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Fuchs, Elaine
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 160
- Issue
- 5
- Pages
- 963-976
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4509607
- OpenAlex
- W2120246444
- Cited by
- 471
- References
- 52
- Citations by year
- 2026: 18 · 2025: 25 · 2024: 35 · 2023: 46 · 2022: 40 · 2021: 60 · 2020: 51 · 2019: 52 · 2018: 41 · 2017: 42 · 2016: 46 · 2015: 13
- FWCI
- 20.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- New York State Department of Health
- National Institutes of Health
- Weill Cornell Medical College
- Japan Society for the Promotion of Science
- National Cancer Institute (R00CA178197, K99CA178197)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR031737)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- TGF-beta signaling, squamous cell carcinoma, cancer stem cells, tumor heterogeneity, drug resistance, tumor-stroma interface, tumor vasculature, cell cycle, p21, Nrf2, glutathione metabolism, lineage tracing, malignant progression, tumor invasion, aberrant differentiation
- MeSH terms
- Animals, Carcinoma, Squamous Cell, Cisplatin, Female, Glutathione, Head and Neck Neoplasms, Humans, Mice, Nude, Neoplasm Transplantation, Skin Neoplasms, Tetradecanoylphorbol Acetate, Neoplastic Stem Cells, 9,10-Dimethyl-1,2-benzanthracene, Signal Transduction, Transforming Growth Factor beta, Drug Resistance, Neoplasm, Gene Expression Profiling, NF-E2-Related Factor 2, Mice, Heterografts
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