Extracellular matrix directs phenotypic heterogeneity of activated fibroblasts
Open accessAbstract
Activated fibroblasts are key players in the injury response, tumorigenesis, fibrosis, and inflammation. Dichotomous outcomes in response to varied stroma-targeted therapies in cancer emphasize the need to disentangle the roles of heterogeneous fibroblast subsets in physiological and pathophysiological settings. In wound healing, fibrosis, and myriad tumor types, fibroblast activation protein (FAP) and alpha-smooth muscle actin (αSMA) identify distinct, yet overlapping, activated fibroblast subsets. Prior studies established that FAP Hi reactive fibroblasts and αSMA Hi myofibroblasts can exert opposing influences in tumorigenesis. However, the factors that drive this phenotypic heterogeneity and the unique functional roles of these subsets have not been defined. We demonstrate that a convergence of ECM composition, elasticity, and transforming growth factor beta (TGF-β) signaling governs activated fibroblast phenotypic heterogeneity. Furthermore, FAP Hi reactive fibroblasts and αSMA Hi myofibroblasts exhibited distinct gene expression signatures and functionality in vitro, illuminating potentially unique roles of activated fibroblast subsets in tissue remodeling. These insights into activated fibroblast heterogeneity will inform the rational design of stroma-targeted therapies for cancer and fibrosis.
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Physical changes in the ECM are capable of activating CAFs.
“Physical changes in the ECM are also capable of activating CAFs53,61–64.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [64]
The Results (§1.2.2; page unavailable) show that changing substrate stiffness shifts cultured fibroblasts between activated phenotypes. The Discussion (§1.3; page unavailable) suggests similar regulation likely occurs in tumors, but the study does not directly show that physical ECM changes activate cancer-associated fibroblasts in tumors. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe αSMA-high, matrix-producing-high state is reversible, supported by the responsiveness of matrix production and the αSMA promoter to extracellular cues including substrate stiffness.
“the responsiveness of matrix production by fibroblasts and the αSMA promoter to a range of extracellular cues, including substrate stiffness, supports the idea that the αSMA-high, matrix producing-high state is reversible63,64,137–139.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [64]
Results §1.2.3 shows that fibroblast morphology and αSMA-enriched populations change when cells are moved between soft and stiff substrates, supporting phenotypic reversibility. Results §1.2.6 links matrix-component expression to substrate-associated fibroblast subsets, but finds greater ECM synthesis in FAP-high cells than in αSMA-high cells. The paper does not demonstrate responsiveness of the αSMA promoter or reversibility of a specifically αSMA-high, matrix-producing-high state. (LLM, conf=0.88)
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A framework for advancing our understanding of cancer-associated fibroblasts
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- Authors
- Avery, D., Govindaraju, P., Jacob, M., Todd, L., Monslow, J., & Puré, E.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Puré, Ellen
- Venue
- Matrix Biology
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 67
- Pages
- 90-106
- ISSN
- 0945-053X (ISSN-L)
- PMC
- PMC5910258
- OpenAlex
- W2774304513
- Cited by
- 206
- References
- 97
- Citations by year
- 2026: 19 · 2025: 22 · 2024: 22 · 2023: 29 · 2022: 34 · 2021: 27 · 2020: 34 · 2019: 10 · 2018: 8
- FWCI
- 5.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Matrix Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Health (R01CA141144, R21CA169741, R01CA172921)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Keywords
- activated fibroblasts, phenotypic heterogeneity, extracellular matrix, fibroblast activation protein, alpha-smooth muscle actin, myofibroblasts, TGF-beta signaling, matrix elasticity, stroma-targeted therapy, tumor microenvironment, fibrosis, tissue remodeling, gene expression signatures
- MeSH terms
- Fibroblast Activation Protein Alpha, Actins, Animals, Cell Differentiation, Cells, Cultured, Extracellular Matrix, Fibroblasts, Membrane Proteins, Endopeptidases, Phenotype, Serine Endopeptidases, Signal Transduction, Transforming Growth Factor beta, Gelatinases, Mice, Myofibroblasts
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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