Abstract
Collective cell migration occurs in a range of contexts: cancer cells frequently invade in cohorts while retaining cell–cell junctions. Here we show that collective invasion by cancer cells depends on decreasing actomyosin contractility at sites of cell–cell contact. When actomyosin is not downregulated at cell–cell contacts, migrating cells lose cohesion. We provide a molecular mechanism for this downregulation. Depletion of discoidin domain receptor 1 (DDR1) blocks collective cancer-cell invasion in a range of two-dimensional, three-dimensional and 'organotypic' models. DDR1 coordinates the Par3/Par6 cell-polarity complex through its carboxy terminus, binding PDZ domains in Par3 and Par6. The DDR1–Par3/Par6 complex controls the localization of RhoE to cell–cell contacts, where it antagonizes ROCK-driven actomyosin contractility. Depletion of DDR1, Par3, Par6 or RhoE leads to increased actomyosin contactility at cell–cell contacts, a loss of cell–cell cohesion and defective collective cell invasion.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Friedl, P., Hegerfeldt, Y. & Tusch, M. Collective cell migration in morphogenesis and cancer. Int. J. Dev. Biol. 48, 441–449 (2004).
Friedl, P. & Gilmour, D. Collective cell migration in morphogenesis, regeneration and cancer. Nat. Rev. Mol. Cell Biol. 10, 445–457 (2009).
DiCostanzo, D., Rosen, P. P., Gareen, I., Franklin, S. & Lesser, M. Prognosis in infiltrating lobular carcinoma. An analysis of 'classical' and variant tumors. Am. J. Surg. Pathol. 14, 12–23 (1990).
Yamamoto, E., Kohama, G., Sunakawa, H., Iwai, M. & Hiratsuka, H. Mode of invasion, bleomycin sensitivity, and clinical course in squamous cell carcinoma of the oral cavity. Cancer 51, 2175–2180 (1983).
Wolf, K. et al. Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat. Cell Biol. 9, 893–904 (2007).
Gaggioli, C. et al. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 9, 1392–1400 (2007).
Hooper, S., Gaggioli, C. & Sahai, E. A chemical biology screen reveals a role for Rab21-mediated control of actomyosin contractility in fibroblast-driven cancer invasion. Br. J. Cancer 102, 392–402 (2010).
Scott, R. W. et al. LIM kinases are required for invasive path generation by tumor and tumor-associated stromal cells. J. Cell Biol. 191, 169–185 (2010).
Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 141, 1117–1134 (2010).
Shattil, S. J., Kim, C. & Ginsberg, M. H. The final steps of integrin activation: the end game. Nat. Rev. Mol. Cell Biol. 11, 288–300 (2010).
Gumbiner, B. M. Regulation of cadherin-mediated adhesion in morphogenesis. Nat. Rev. Mol. Cell Biol. 6, 622–634 (2005).
Johnson, J. D., Edman, J. C. & Rutter, W. J. A receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin I-like domain. Proc. Natl Acad. Sci. USA 90, 5677–5681 (1993).
Vogel, W., Gish, G. D., Alves, F. & Pawson, T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol. Cell 1, 13–23 (1997).
Shrivastava, A. et al. An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol. Cell 1, 25–34 (1997).
Wang, C. Z., Yeh, Y. C. & Tang, M. J. DDR1/E-cadherin complex regulates the activation of DDR1 and cell spreading. Am. J. Physiol. Cell Physiol. 297, C419–C429 (2009).
Croft, D. R. et al. Conditional ROCK activation in vivo induces tumor cell dissemination and angiogenesis. Cancer Res. 64, 8994–9001 (2004).
Simpson, K. J. et al. Identification of genes that regulate epithelial cell migration using an siRNA screening approach. Nat.Cell Biol. 10, 1027–1038 (2008).
Zhang, J. et al. Actin at cell–cell junctions is composed of two dynamic and functional populations. J. Cell Sci. 118, 5549–5562 (2005).
Leitinger, B. Molecular analysis of collagen binding by the human discoidin domain receptors, DDR1 and DDR2. Identification of collagen binding sites in DDR2. J. Biol. Chem. 278, 16761–16769 (2003).
Vogel, W. et al. Discoidin domain receptor 1 is activated independently of β1 integrin. J. Biol. Chem. 275, 5779–5784 (2000).
Abdulhussein, R., McFadden, C., Fuentes-Prior, P. & Vogel, W. F. Exploring the collagen-binding site of the DDR1 tyrosine kinase receptor. J. Biol. Chem. 279, 31462–31470 (2004).
Itoh, M. et al. Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins. J. Cell Biol. 147, 1351–1363 (1999).
Goldstein, B. & Macara, I. G. The PAR proteins: fundamental players in animal cell polarization. Dev .Cell 13, 609–622 (2007).
Izumi, Y. et al. An atypical PKC directly associates and colocalizes at the epithelial tight junction with ASIP, a mammalian homologue of Caenorhabditis elegans polarity protein PAR-3. J. Cell Biol. 143, 95–106 (1998).
Joberty, G., Petersen, C., Gao, L. & Macara, I. G. The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nat. Cell Biol. 2, 531–539 (2000).
Mertens, A. E., Rygiel, T. P., Olivo, C., van der Kammen, R. & Collard, J. G. The Rac activator Tiam1 controls tight junction biogenesis in keratinocytes through binding to and activation of the Par polarity complex. J. Cell Biol. 170, 1029–1037 (2005).
Wildenberg, G. A. et al. p120-catenin and p190RhoGAP regulate cell–cell adhesion by coordinating antagonism between Rac and Rho. Cell 127, 1027–1039 (2006).
Riento, K., Guasch, R. M., Garg, R., Jin, B. & Ridley, A. J. RhoE binds to ROCK I and inhibits downstream signaling. Mol. Cell. Biol. 23, 4219–4229 (2003).
Pinner, S. & Sahai, E. PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE. Nat. Cell Biol. 10, 127–137 (2008).
Wennerberg, K. et al. Rnd proteins function as RhoA antagonists by activating p190 RhoGAP. Curr. Biol. 13, 1106–1115 (2003).
Foster, R. et al. Identification of a novel human Rho protein with unusual properties: GTPase deficiency and in vivo farnesylation. Mol. Cell. Biol. 16, 2689–2699 (1996).
Danjo, Y. & Gipson, I. K. Actin 'purse string' filaments are anchored by E-cadherin-mediated adherens junctions at the leading edge of the epithelial wound, providing coordinated cell movement. J. Cell Sci. 111, 3323–3332 (1998).
Benink, H. A. & Bement, W. M. Concentric zones of active RhoA and Cdc42 around single cell wounds. J. Cell Biol. 168, 429–439 (2005).
Wood, W. et al. Wound healing recapitulates morphogenesis in Drosophila embryos. Nat. Cell Biol. 4, 907–912 (2002).
Carmona-Fontaine, C. et al. Contact inhibition of locomotion in vivo controls neural crest directional migration. Nature 456, 957–961 (2008).
Sahin, M. et al. Eph-dependent tyrosine phosphorylation of ephexin1 modulates growth cone collapse. Neuron 46, 191–204 (2005).
Dow, L. E. et al. The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge. Oncogene 26, 2272–2282 (2007).
Etienne-Manneville, S., Manneville, J. B., Nicholls, S., Ferenczi, M. A. & Hall, A. Cdc42 and Par6-PKCζ regulate the spatially localized association of Dlg1 and APC to control cell polarization. J. Cell Biol. 170, 895–901 (2005).
Osmani, N., Vitale, N., Borg, J. P. & Etienne-Manneville, S. Scrib controls Cdc42 localization and activity to promote cell polarization during astrocyte migration. Curr. Biol. 16, 2395–2405 (2006).
Schmoranzer, J. et al. Par3 and dynein associate to regulate local microtubule dynamics and centrosome orientation during migration. Curr. Biol. 19, 1065–1074 (2009).
Pinheiro, E. M. & Montell, D. J. Requirement for Par-6 and Bazooka in Drosophila border cell migration. Development 131, 5243–5251 (2004).
Zhang, H. & Macara, I. G. The PAR-6 polarity protein regulates dendritic spine morphogenesis through p190 RhoGAP and the Rho GTPase. Dev. Cell 14, 216–226 (2008).
Riento, K., Villalonga, P., Garg, R. & Ridley, A. Function and regulation of RhoE. Biochem. Soc. Trans. 33, 649–651 (2005).
Peacock, J. G. et al. The Abl-related gene tyrosine kinase acts through p190RhoGAP to inhibit actomyosin contractility and regulate focal adhesion dynamics upon adhesion to fibronectin. Mol. Biol. Cell 18, 3860–3872 (2007).
Nakayama, M. et al. Rho-kinase phosphorylates PAR-3 and disrupts PAR complex formation. Dev. Cell 14, 205–215 (2008).
Simões Sde, M. et al. Rho-kinase directs Bazooka/Par-3 planar polarity during Drosophila axis elongation. Dev. Cell 19, 377–388 (2010).
Reynolds, A. B. p120-catenin: past and present. Biochim. Biophys. Acta 1773, 2–7 (2007).
Schimanski, C. C. et al. Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer. Oncogene 24, 3100–3109 (2005).
Kuphal, S. et al. Expression of Hugl-1 is strongly reduced in malignant melanoma. Oncogene 25, 103–110 (2006).
Gardiol, D., Zacchi, A., Petrera, F., Stanta, G. & Banks, L. Human discs large and scrib are localized at the same regions in colon mucosa and changes in their expression patterns are correlated with loss of tissue architecture during malignant progression. Int J Cancer 119, 1285–1290 (2006).
Shimada, K. et al. Prostate cancer antigen-1 contributes to cell survival and invasion though discoidin receptor 1 in human prostate cancer. Cancer Sci. 99, 39–45 (2008).
Huang, Y., Arora, P., McCulloch, C. A. & Vogel, W. F. The collagen receptor DDR1 regulates cell spreading and motility by associating with myosin IIA. J. Cell Sci. 122, 1637–1646 (2009).
Rheinwald, J. G. & Beckett, M. A. Tumorigenic keratinocyte lines requiring anchorage and fibroblast support cultures from human squamous cell carcinomas. Cancer Res. 41, 1657–1663 (1981).
Acknowledgements
We thank Cancer Research UK and EMBO for funding and B. Thompson, N. Tapon and lab members for comments and discussion. We also thank the Experimental Pathology lab for technical help.
Author information
Authors and Affiliations
Contributions
C.H.C. and E.S. conceived and designed the experiments. C.H.C. performed all experiments except Figs 1a, e and 5c, d, f. Supplementary Information, Figures S1, S2 and S5c were performed by E.S. Fig 4b and various molecular cloning procedures were performed by S.H. The clinical samples used in Supplementary Information, Figures S1 and S6 were collected by S.I.C., P.W. and K.H.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Information
Supplementary Information (PDF 1615 kb)
Supplementary Movie 1
Supplementary Information (AVI 8663 kb)
Supplementary Movie 2
Supplementary Information (AVI 9816 kb)
Supplementary Movie 3
Supplementary Information (AVI 5595 kb)
Supplementary Movie 4
Supplementary Information (AVI 5626 kb)
Supplementary Movie 5
Supplementary Information (AVI 2320 kb)
Rights and permissions
About this article
Cite this article
Hidalgo-Carcedo, C., Hooper, S., Chaudhry, S. et al. Collective cell migration requires suppression of actomyosin at cell–cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. Nat Cell Biol 13, 49–59 (2011). https://doi.org/10.1038/ncb2133
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ncb2133
This article is cited by
-
Inactivation of kindlin-3 increases human melanoma aggressiveness through the collagen-activated tyrosine kinase receptor DDR1
Oncogene (2024)
-
An in vitro culture platform for studying the effect of collective cell migration on spatial self-organization within induced pluripotent stem cell colonies
Journal of Biological Engineering (2023)
-
Accelerating material design with the generative toolkit for scientific discovery
npj Computational Materials (2023)
-
A network map of discoidin domain receptor 1(DDR1)-mediated signaling in pathological conditions
Journal of Cell Communication and Signaling (2023)
-
Physics of collective cell migration
European Biophysics Journal (2023)