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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Carcinoma cells undergoing EMT tend to be more resistant to chemotherapy.
“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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- 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 · 2014: 2
- 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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