A chemical biology screen reveals a role for Rab21-mediated control of actomyosin contractility in fibroblast-driven cancer invasion
Open accessAbstract
BACKGROUND: Carcinoma-associated fibroblasts (CAFs) can promote the progression of tumours in many ways. They can remodel the extracellular matrix to generate an environment that enables the invasion of cancer cells. We hypothesised that compounds that prevent matrix remodelling by CAFs would block their ability to promote carcinoma cell invasion. METHODS: We designed a screen for compounds that interfere with CAF-promoted matrix remodelling. Hits from this screen were investigated in organotypic invasion models of squamous cell carcinoma (SCC). RESULTS: We find that lovastatin and simvastatin reduce matrix remodelling by fibroblasts and thereby reduce SCC invasion. This class of compounds exert their effects partly through disrupting the function of Rab proteins, and we show a new role for Rab21 in promoting cancer cell invasion promoted by CAFs. CONCLUSIONS: Rab21 is required for CAFs to promote the invasion of cancer cells. It enables the accumulation of integrin alpha5 at the plasma membrane and subsequent force-mediated matrix remodelling.
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CAF ECM deposition and remodelling depends on RHO and RAB GTPase-mediated control of integrin-mediated adhesions and the actomyosin cytoskeleton and is linked to downregulation of CD36.
“This depends on RHO and RAB GTPase-mediated control of integrin-mediated adhesions and the actomyosin cytoskeleton81–83 and is linked to downregulation of the transmembrane receptor CD36 (also known as platelet glycoprotein 4)84.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [83]
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A framework for advancing our understanding of cancer-associated fibroblasts
Sahai, E., Astsaturov, I., Cukierman, E., DeNardo, D. G., Egeblad, M., Evans, R. M., Fearon, D., Greten, F. R., Hingorani, S. R., Hunter, T., et al. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0238-1 · Cited by 3,863 · see citing works
Self-citationHypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis
Madsen, C. D., Pedersen, J. T., Venning, F. A., Singh, L. B., Moeendarbary, E., Charras, G., Cox, T. R., Sahai, E., & Erler, J. T. (2015) · The EMBO Reports · doi:10.15252/embr.201540107 · Cited by 157 · see citing works
Self-citation
- Authors
- Hooper, S., Gaggioli, C., & Sahai, E.
- Affiliations
- Cancer Research UK (GB)
- Inserm (FR)
- Corresponding author
- Sahai, E
- Venue
- British Journal of Cancer
- Published
- 2009-12-01
- Volume
- 102
- Issue
- 2
- Pages
- 392-402
- ISSN
- 0007-0920 (ISSN-L)
- 1532-1827
- PMC
- PMC2816649
- OpenAlex
- W2010645803
- Cited by
- 80
- References
- 2
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 7 · 2019: 6 · 2018: 2 · 2017: 6 · 2016: 4 · 2015: 7 · 2014: 3 · 2013: 4 · 2012: 8
- FWCI
- 2.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (unspecified)
- Locations
- British Journal of Cancer (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Cancer Research UK
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- Rab21, cancer-associated fibroblasts, tumor invasion, actomyosin contractility, extracellular matrix remodeling, squamous cell carcinoma, lovastatin, simvastatin, statins, integrin alpha5, Rab GTPases
- MeSH terms
- Actomyosin, Carcinoma, Squamous Cell, Extracellular Matrix, Fibroblasts, Humans, Lovastatin, Muscle Contraction, Neoplasm Invasiveness, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, rab GTP-Binding Proteins, Integrin alpha5
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