Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts
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To learn more about cancer-associated fibroblasts (CAFs), we have isolated fibroblasts from different stages of breast cancer progression and analysed their function and gene expression. These analyses reveal that activation of the YAP transcription factor is a signature feature of CAFs. YAP function is required for CAFs to promote matrix stiffening, cancer cell invasion and angiogenesis. Remodelling of the ECM and promotion of cancer cell invasion requires the actomyosin cytoskeleton. YAP regulates the expression of several cytoskeletal regulators, including ANLN and DIAPH3, and controls the protein levels of MYL9 (also known as MLC2). Matrix stiffening further enhances YAP activation, thus establishing a feed-forward self-reinforcing loop that helps to maintain the CAF phenotype. Actomyosin contractility and Src function are required for YAP activation by stiff matrices. Further, transient ROCK inhibition is able to disrupt the feed-forward loop, leading to a long-lasting reversion of the CAF phenotype.
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Well-established activating signals for fibroblasts include TGFβ family ligands and LPA, which promote SMAD and SRF respectively, and converge to drive αSMA expression and increase contractile cytoskeleton activity.
“Well-established activating signals for fibroblasts include TGFβ family ligands and the lipid mediator lysophosphatidic acid52–54, which promote the activity of the SMAD transcription factors and serum response factor (SRF), respectively, and converge to drive expression of the activated fibroblast marker αSMA as well as increase the activity of the contractile cytoskeleton6”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [53]
The Results section on actomyosin contractility (page unavailable) calls LPA and TGFβ pro-contractile stimuli and reports that they promote matrix remodelling in fibroblasts. The Results also reports increased SRF-associated gene expression in CAFs, but our copy does not establish the claimed TGFβ–SMAD and LPA–SRF pathways or show that these signals converge to induce αSMA expression. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMatricellular molecules such as CTGF and CYR61 and the contractile cytoskeleton cooperate to increase tissue stiffness, which further drives SRF-dependent and YAP1-dependent transcriptional programmes, locking CAFs into a self-sustaining positive-feedback loop.
“Furthermore, matricellular molecules, such as CTGF and CYR61, and the contractile cytoskeleton cooperate to increase tissue stiffness, which further drives SRF-dependent and YAP1-dependent transcriptional programmes, locking CAFs into a self-sustaining positive-feedback loop53.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [53]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn vitro studies have shown that fibroblast stretching can activate SRF-driven transcription and YAP1-TEAD-driven transcription.
“In vitro studies have shown that fibroblast stretching, which may result from the hyperproliferation of transformed epithelial cells, can activate SRF-driven transcription and Yes-associated protein 1 (YAP1)–TEAD-driven transcription53,54,65,66.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [53]
The Results section (“YAP is activated CAFs”; page unavailable) reports increased expression of genes associated with the mechanosensitive YAP/TAZ and SRF pathways in cultured fibroblasts. The Results section on actomyosin contractility also links matrix stiffness to YAP–TEAD association. The paper does not show that stretching fibroblasts activates both transcriptional pathways, or establish epithelial hyperproliferation as the cause of such stretching. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCAFs secrete MMPs including MMP-2, MMP-3, and MMP-9, or activate Yes-associated protein to promote ECM degradation and remodeling, EMT, and CSC stemness.
“CAFs reportedly secrete matrix metalloproteinases (MMPs), including MMP-2, MMP-3, and MMP-9, or activate Yes-associated protein to promote ECM degradation and remodeling, EMT, and CSC stemness.283–287”
From Drug repurposing for cancer therapy (2024) · cites this paper as [284]
The Results section on YAP and the contractile actomyosin cytoskeleton reports that YAP enables CAF-driven ECM remodelling and cancer-cell invasion. The paper does not report secretion of MMP-2, MMP-3, or MMP-9, ECM degradation, or CAF-induced EMT; its Introduction associates YAP/TAZ activity with cancer stem-cell properties but does not establish that CAF YAP activation promotes CSC stemness. Page numbers were unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredFormation of context-dependent Yki/YAP-mediated signalling loops is a bona fide mechanism for tumour growth.
“The biological significance of our findings is validated by other studies that show formation of context-dependent Yki/YAP-mediated signalling loops as a bona fide mechanism for tumour growth (68,69).”
From A Tumour-Specific Molecular Network Promotes Tumour Growth in <i>Drosophila</i> by Enforcing a JNK-YKI Feedforward Loop (2023) · cites this paper as [68]
The Results (‘A positive feedback loop involving actomyosin contractility sustains YAP activation’; page unavailable) and Discussion describe a YAP–matrix-stiffening feedback loop in cancer-associated fibroblasts. The Results (‘YAP is required for CAF function’; page unavailable) link YAP to tumour-promoting invasion and angiogenesis, but the copy does not establish that this loop drives tumour growth itself or examine Yki. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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 [53]
Certain CAF characteristics are stably maintained in culture, such as increased ability to remodel the ECM.
“certain CAF characteristics are stably maintained in culture, such as their increased ability to remodel the ECM53”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [53]
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- Authors
- Calvo, F., Ege, N., Grande-Garcia, A., Hooper, S., Jenkins, R. P., Chaudhry, S. I., Harrington, K., Williamson, P., Moeendarbary, E., Charras, G., & Sahai, E.
- Affiliations
- Cancer Research UK (GB)
- Queen Mary University of London (GB)
- Institute of Cancer Research (GB)
- St George's Hospital (GB)
- London Centre for Nanotechnology (GB)
- Corresponding author
- Sahai, Erik
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2013-05-26
- Volume
- 15
- Issue
- 6
- Pages
- 637-646
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC3836234
- OpenAlex
- W2033998652
- Cited by
- 1,478
- References
- 58
- Citations by year
- 2026: 133 · 2025: 117 · 2024: 122 · 2023: 145 · 2022: 146 · 2021: 149 · 2020: 129 · 2019: 106 · 2018: 115 · 2017: 100 · 2016: 82 · 2015: 67 · 2014: 58 · 2013: 9
- FWCI
- 41.66
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Cancer Research UK (15154, A5317)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- cancer-associated fibroblasts, YAP, mechanotransduction, extracellular matrix remodeling, matrix stiffening, breast cancer progression, actomyosin contractility, Src kinase, ROCK inhibition, feed-forward loop, anillin, DIAPH3, MYL9, tumor invasion, angiogenesis
- MeSH terms
- YAP-Signaling Proteins, Actomyosin, Animals, Breast Neoplasms, Cells, Cultured, Enzyme Activation, Extracellular Matrix, Female, Fibroblasts, Humans, Actin Cytoskeleton, Microtubule-Associated Proteins, NADPH Dehydrogenase, Neoplasm Invasiveness, Neovascularization, Pathologic, Phosphoproteins, Phosphorylation, Disease Progression, Microscopy, Atomic Force, Cell Cycle Proteins, Myosin Light Chains, src-Family Kinases, Focal Adhesions, RNA Interference, RNA, Small Interfering, Mechanotransduction, Cellular, Adaptor Proteins, Signal Transducing, Mice, rho-Associated Kinases
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