Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells
Abstract
Imaging of collectively invading cocultures of carcinoma cells and stromal fibroblasts reveals that the leading cell is always a fibroblast and that carcinoma cells move within tracks in the extracellular matrix behind the fibroblast. The generation of these tracks by fibroblasts is sufficient to enable the collective invasion of the squamous cell carcinoma (SCC) cells and requires both protease- and force-mediated matrix remodelling. Force-mediated matrix remodelling depends on integrins alpha3 and alpha5, and Rho-mediated regulation of myosin light chain (MLC) activity in fibroblasts, but these factors are not required in carcinoma cells. Instead, carcinoma cells use Cdc42 and MRCK (myotonic dystrophy kinase-related CDC42-binding protein kinases) mediated regulation of MLC to follow the tracks generated by fibroblasts.
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CAFs are key contributors to ECM remodeling, angiogenesis, and metastasis.
“These CAFs are characterized by the expression of specific markers, such as desmin and fibroblast activation protein, and are now recognized as key contributors to ECM remodeling, angiogenesis, and metastasis [36,37,38,39,40].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [37]
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 [81]
Production of matrix proteases allows the tumour matrix to be remodelled, which can lead to generation of permissive tracks that allow cancer cell invasion.
“Although chemical crosslinks are not readily reversed, the production of matrix proteases allows the tumour matrix to be remodelled, and this can lead to the generation of permissive tracks that allow cancer cell invasion81.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [81]
CAFs secrete growth factors, proinflammatory cytokines, and chemokines, particularly TGF-β, IL-6, and CCL2, which recruit immunosuppressive cells into the tumor stroma and lead to immune escape.
“In addition, CAFs secrete substantial amounts of growth factors, proinflammatory cytokines, and chemokines, particularly TGF-β, IL-6, and CC-chemokine ligand 2, which recruit immunosuppressive cells into the tumor stroma and lead to immune escape 20-22.”
From TBX3 shapes an immunosuppressive microenvironment and induces immunotherapy resistance (2025) · cites this paper as [22]
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“Interestingly, fibroblasts can support collective invasion by squamous cell carcinoma cells that are otherwise unable to invade (Gaggioli et al., 2007; Zhang et al., 2006).”
BackgroundRho GTPases and their role in organizing the actin cytoskeleton
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“It is notable that fibroblast migration through a three-dimensional extracellular matrix requires ROCK, whereas carcinoma cells rely primarily on MRCK (Gaggioli et al., 2007); in other contexts, PAKs are implicated in cancer cell migration (Molli et al., 2009).”
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“It has been reported CAFs enhance the invasion of cancer cells via various mechanisms, such as MMP-mediated ECM degradation and subsequent release of latent growth factors [22]; matrix stiffening through integrin-mediated mechanotransduction and through actomyosin contractility [150, 350]; secretion of soluble factors…”
BackgroundDirected cell invasion and migration during metastasis
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“com (invadopodia) and locomotory protrusions (pseudopodia) is regulated by stromal cells in the tumor microenvironment including fibroblasts (squamos cell carcinoma) [45] and macrophages (breast carcinoma) [21 ].”
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“Breach of the basement membrane can be accomplished by MMP-based proteolysis by the cancer cells (10, 39), by immune cells recruited during inflammatory processes, or by the actions of carcinoma-associated macrophages (40) or fibroblasts (41).”
BackgroundMechanobiology and Developmental Control
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“The invasive behaviour of the squamous carcinoma cells was dependent on the fibroblasts (Gaggioli et al. 2007).”
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“On the other hand, CAFs physically remodel the ECMand lead cancer cell invasion [41,42].”
BackgroundCollective cell migration: guidance principles and hierarchies
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“[22] demonstrated that CAFs generate force- and protease-mediated tracks into ECM, and cancer cells follow these leading fibroblasts along the tracks.”
BackgroundFroeling, F. E. M., Feig, C., Chelala, C., Dobson, R., Mein, C. A., Tuveson, D. A., Clevers, H. C., Hart, I. R., & Kocher, H. M. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.06.047 · Cited by 421 · see citing works
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“Structural ECM organization influences melanoma cell invasion Cell motility is thought to be a function of stiffness of the matrix as well as intrinsic invasiveness of the cells (32-34).”
BackgroundOncogene-like induction of cellular invasion from centrosome amplification
Godinho, S. A., Picone, R., Burute, M., Dagher, R., Su, Y., Leung, C. T., Polyák, K., Brugge, J. S., Théry, M., & Pellman, D. S. (2014) · Nature · doi:10.1038/nature13277 · Cited by 416 · see citing works
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“Since stromal fibroblasts can play an important role in tumor invasiveness27,28, we also tested the requirement for MRTF-SRF activity in an organotypic invasion model, in which tumour cells move through collagen gel along tracks generated by stromal carcinoma-associated fibroblasts (CAFs)29.”
ROCK and JAK1 Signaling Cooperate to Control Actomyosin Contractility in Tumor Cells and Stroma
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“Here, an individual ‘leader’ cell utilizes focalized proteolysis by the surfacecollagenase MT1-MMP to generate tracks of least mechanical resistance that enable the cell mass to undergo subsequent collective invasion (Wolf et al., 2007).”
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“The blockade of integrin α 3, α 5, or Rho-Rock function in CAFs reduces the formation of these tracks and hampers cancer cell invasion (10).”
BackgroundCell–cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion
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Background
- Authors
- Gaggioli, C., Hooper, S., Hidalgo-Carcedo, C., Grosse, R., Marshall, J. F., Harrington, K., & Sahai, E.
- Affiliations
- Cancer Research UK (GB)
- Heidelberg University (DE)
- Queen Mary University of London (GB)
- Institute of Cancer Research (GB)
- Corresponding author
- Sahai, Erik
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2007-11-25
- Volume
- 9
- Issue
- 12
- Pages
- 1392-1400
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W1977381126
- Cited by
- 1,589
- References
- 32
- Citations by year
- 2026: 57 · 2025: 75 · 2024: 70 · 2023: 108 · 2022: 97 · 2021: 110 · 2020: 117 · 2019: 106 · 2018: 93 · 2017: 100 · 2016: 86 · 2015: 87 · 2014: 92 · 2013: 79 · 2012: 80
- FWCI
- 20.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- 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
- collective invasion, carcinoma cells, stromal fibroblasts, Rho GTPases, Cdc42, MRCK, myosin light chain, integrin alpha3, integrin alpha5, extracellular matrix remodeling, squamous cell carcinoma, cell tracks
- MeSH terms
- Carcinoma, Squamous Cell, Cell Movement, Cells, Cultured, Extracellular Matrix, Fibroblasts, Heat-Shock Proteins, Humans, Neoplasm Invasiveness, Myosin Light Chains, rho GTP-Binding Proteins, cdc42 GTP-Binding Protein, Integrin alpha3, Integrin alpha5, HSP27 Heat-Shock Proteins
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