Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Decoding leader cells in collective cancer invasion

Nature Reviews Cancer volume 21, pages 592–604 (2021)Cite this article

Subjects

Abstract

Collective cancer invasion with leader–follower organization is increasingly recognized as a predominant mechanism in the metastatic cascade. Leader cells support cancer invasion by creating invasion tracks, sensing environmental cues and coordinating with follower cells biochemically and biomechanically. With the latest developments in experimental and computational models and analysis techniques, the range of specific traits and features of leader cells reported in the literature is rapidly expanding. Yet, despite their importance, there is no consensus on how leader cells arise or their essential characteristics. In this Perspective, we propose a framework for defining the essential aspects of leader cells and provide a unifying perspective on the varying cellular and molecular programmes that are adopted by each leader cell subtype to accomplish their functions. This Perspective can lead to more effective strategies to interdict a major contributor to metastatic capability.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Leader cell categories and key functions.
Fig. 2: Path generation.
Fig. 3: Cell–cell coordination and guidance.
Fig. 4: Survival and metastasis.

Similar content being viewed by others

References

  1. Friedl, P., Locker, J., Sahai, E. & Segall, J. E. Classifying collective cancer cell invasion. Nat. Cell Biol. 14, 777–783 (2012).

    Article  PubMed  CAS  Google Scholar 

  2. Liotta, L. A., Saidel, M. G. & Kleinerman, J. The significance of hematogenous tumor cell clumps in the metastatic process. Cancer Res. 36, 889–894 (1976).

    CAS  PubMed  Google Scholar 

  3. Friedl, P. et al. Migration of coordinated cell clusters in mesenchymal and epithelial cancer explants in vitro. Cancer Res. 55, 4557–4560 (1995).

    CAS  PubMed  Google Scholar 

  4. Aceto, N. et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158, 1110–1122 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nagai, T., Ishikawa, T., Minami, Y. & Nishita, M. Tactics of cancer invasion: solitary and collective invasion. J. Biochem. 167, 347–355 (2020).

    Article  CAS  PubMed  Google Scholar 

  6. Mayor, R. & Etienne-Manneville, S. The front and rear of collective cell migration. Nat. Rev. Mol. Cell Biol. 17, 97–109 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Chen, B. J., Wu, J. S., Tang, Y. J., Tang, Y. L. & Liang, X. H. What makes leader cells arise: intrinsic properties and support from neighboring cells. J. Cell. Physiol. 235, 8983–8995 (2020).

    Article  CAS  PubMed  Google Scholar 

  8. Zoeller, E. L. et al. Genetic heterogeneity within collective invasion packs drives leader and follower cell phenotypes. J. Cell Sci. 132, jcs231514 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Westcott, J. M. et al. An epigenetically distinct breast cancer cell subpopulation promotes collective invasion. J. Clin. Invest. 125, 1927–1943 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  10. 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).

    Article  CAS  PubMed  Google Scholar 

  11. Siegel, R. L., Miller, K. D., Fuchs, H. E. & Jemal, A. Cancer statistics, 2021. CA Cancer J. Clin. 71, 7–33 (2021).

    Article  PubMed  Google Scholar 

  12. Vishwakarma, M., Spatz, J. P. & Das, T. Mechanobiology of leader-follower dynamics in epithelial cell migration. Curr. Opin. Cell Biol. 66, 97–103 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. Winkler, J., Abisoye-Ogunniyan, A., Metcalf, K. J. & Werb, Z. Concepts of extracellular matrix remodelling in tumour progression and metastasis. Nat. Commun. 11, 5120 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. van Helvert, S., Storm, C. & Friedl, P. Mechanoreciprocity in cell migration. Nat. Cell Biol. 20, 8–20 (2018).

    Article  PubMed  CAS  Google Scholar 

  15. Bocci, F., Levine, H., Onuchic, J. N. & Jolly, M. K. Deciphering the dynamics of epithelial–mesenchymal transition and cancer stem cells in tumor progression. Curr. Stem Cell Rep. 5, 11–21 (2019).

    Article  Google Scholar 

  16. Thiery, J. P. Epithelial–mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442–454 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Jolly, M. K., Ware, K. E., Gilja, S., Somarelli, J. A. & Levine, H. EMT and MET: necessary or permissive for metastasis? Mol. Oncol. 11, 755–769 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Konen, J. et al. Image-guided genomics of phenotypically heterogeneous populations reveals vascular signalling during symbiotic collective cancer invasion. Nat. Commun. 8, 15078 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Saenz-de-Santa-Maria, I., Celada, L. & Chiara, M. D. The leader position of mesenchymal cells expressing N-cadherin in the collective migration of epithelial cancer. Cells 9, 731 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  20. Riahi, R. et al. Single cell gene expression analysis in injury-induced collective cell migration. Integr. Biol. 6, 192–202 (2014).

    Article  CAS  Google Scholar 

  21. Li, C. F. et al. Snail-induced claudin-11 prompts collective migration for tumour progression. Nat. Cell Biol. 21, 251–262 (2019).

    Article  CAS  PubMed  Google Scholar 

  22. Bocci, F. et al. NRF2 activates a partial epithelial–mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype. Integr. Biol. 11, 251–263 (2019).

    Article  Google Scholar 

  23. Carey, S. P., Starchenko, A., McGregor, A. L. & Reinhart-King, C. A. Leading malignant cells initiate collective epithelial cell invasion in a three-dimensional heterotypic tumor spheroid model. Clin. Exp. Metastasis 30, 615–630 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Revenu, C. & Gilmour, D. EMT 2.0: shaping epithelia through collective migration. Curr. Opin. Genet. Dev. 19, 338–342 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Brabletz, T., Kalluri, R., Nieto, M. A. & Weinberg, R. A. EMT in cancer. Nat. Rev. Cancer 18, 128–134 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Nieto, M. A., Huang, R. Y., Jackson, R. A. & Thiery, J. P. EMT: 2016. Cell 166, 21–45 (2016).

    Article  CAS  PubMed  Google Scholar 

  27. Kroger, C. et al. Acquisition of a hybrid E/M state is essential for tumorigenicity of basal breast cancer cells. Proc. Natl Acad. Sci. USA 116, 7353–7362 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lu, M., Jolly, M. K., Levine, H., Onuchic, J. N. & Ben-Jacob, E. MicroRNA-based regulation of epithelial-hybrid-mesenchymal fate determination. Proc. Natl Acad. Sci. USA 110, 18144–18149 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang, J. et al. TGF-beta-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Sci. Signal. 7, ra91 (2014).

    Article  PubMed  CAS  Google Scholar 

  30. Williams, E. D., Gao, D., Redfern, A. & Thompson, E. W. Controversies around epithelial–mesenchymal plasticity in cancer metastasis. Nat. Rev. Cancer 19, 716–732 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pastushenko, I. et al. Identification of the tumour transition states occurring during EMT. Nature 556, 463–468 (2018).

    Article  CAS  PubMed  Google Scholar 

  32. Yu, M. et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580–584 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Quan, Q. H. et al. Cancer stem-like cells with hybrid epithelial/mesenchymal phenotype leading the collective invasion. Cancer Sci. 111, 467–476 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wu, J. S. et al. Cathepsin B defines leader cells during the collective invasion of salivary adenoid cystic carcinoma. Int. J. Oncol. 54, 1233–1244 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Johnson, J. L., Najor, N. A. & Green, K. J. Desmosomes: regulators of cellular signaling and adhesion in epidermal health and disease. Cold Spring Harb. Perspect. Med. 4, a015297 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Choi, W. et al. Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer. Nat. Rev. Urol. 11, 400–410 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Badve, S. et al. Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists. Mod. Pathol. 24, 157–167 (2011).

    Article  PubMed  Google Scholar 

  38. Mazzalupo, S., Wong, P., Martin, P. & Coulombe, P. A. Role for keratins 6 and 17 during wound closure in embryonic mouse skin. Dev. Dyn. 226, 356–365 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Park, M. et al. Visualizing the contribution of keratin-14+ limbal epithelial precursors in corneal wound healing. Stem Cell Rep. 12, 14–28 (2019).

    Article  CAS  Google Scholar 

  40. Cheung, K. J., Gabrielson, E., Werb, Z. & Ewald, A. J. Collective invasion in breast cancer requires a conserved basal epithelial program. Cell 155, 1639–1651 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kanner, W. A., Galgano, M. T. & Atkins, K. A. Podoplanin expression in basal and myoepithelial cells: utility and potential pitfalls. Appl. Immunohistochem. Mol. Morphol. 18, 226–230 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Wicki, A. et al. Tumor invasion in the absence of epithelial–mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell 9, 261–272 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Hwang, P. Y., Brenot, A., King, A. C., Longmore, G. D. & George, S. C. Randomly distributed K14+ breast tumor cells polarize to the leading edge and guide collective migration in response to chemical and mechanical environmental cues. Cancer Res. 79, 1899–1912 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nguyen-Ngoc, K. V. et al. ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium. Proc. Natl Acad. Sci. USA 109, E2595–E2604 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sonzogni, O. et al. Reporters to mark and eliminate basal or luminal epithelial cells in culture and in vivo. PLoS Biol. 16, e2004049 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Dang, T. T. et al. DeltaNp63alpha induces the expression of FAT2 and Slug to promote tumor invasion. Oncotarget 7, 28592–28611 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Karacosta, L. G. et al. Mapping lung cancer epithelial–mesenchymal transition states and trajectories with single-cell resolution. Nat. Commun. 10, 5587 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cook, D. P. & Vanderhyden, B. C. Context specificity of the EMT transcriptional response. Nat. Commun. 11, 2142 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yang, J. et al. Guidelines and definitions for research on epithelial–mesenchymal transition. Nat. Rev. Mol. Cell Biol. 21, 341–352 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. desJardins-Park, H. E., Foster, D. S. & Longaker, M. T. Fibroblasts and wound healing: an update. Regen. Med. 13, 491–495 (2018).

    Article  CAS  PubMed  Google Scholar 

  51. Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Richardson, A. M. et al. Vimentin is required for lung adenocarcinoma metastasis via heterotypic tumor cell-cancer associated fibroblast interactions during collective invasion. Clin. Cancer Res. 24, 420–432 (2018).

    Article  CAS  PubMed  Google Scholar 

  53. Labernadie, A. et al. A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion. Nat. Cell Biol. 19, 224–237 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Theret, M., Mounier, R. & Rossi, F. The origins and non-canonical functions of macrophages in development and regeneration. Development 19, dev156000 (2019).

    Article  CAS  Google Scholar 

  55. Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Zhou, J. et al. Tumor-associated macrophages: recent insights and therapies. Front. Oncol. 10, 188 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Lin, Y., Xu, J. & Lan, H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J. Hematol. Oncol. 12, 76 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Sousa, S. et al. Human breast cancer cells educate macrophages toward the M2 activation status. Breast Cancer Res. 17, 101 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Hollmen, M., Roudnicky, F., Karaman, S. & Detmar, M. Characterization of macrophage — cancer cell crosstalk in estrogen receptor positive and triple-negative breast cancer. Sci. Rep. 5, 9188 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Guiet, R. et al. The process of macrophage migration promotes matrix metalloproteinase-independent invasion by tumor cells. J. Immunol. 187, 3806–3814 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Patsialou, A. et al. Intravital multiphoton imaging reveals multicellular streaming as a crucial component of in vivo cell migration in human breast tumors. Intravital 2, e25294 (2013).

    Article  PubMed  Google Scholar 

  62. Haigo, S. L. & Bilder, D. Global tissue revolutions in a morphogenetic movement controlling elongation. Science 331, 1071–1074 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Attieh, Y. et al. Cancer-associated fibroblasts lead tumor invasion through integrin-beta 3-dependent fibronectin assembly. J. Cell Biol. 216, 3509–3520 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Erdogan, B. et al. Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. J. Cell Biol. 216, 3799–3816 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sangaletti, S. et al. Macrophage-derived SPARC bridges tumor cell-extracellular matrix interactions toward metastasis. Cancer Res. 68, 9050–9059 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Koblinski, J. E. et al. Endogenous osteonectin/SPARC/BM-40 expression inhibits MDA-MB-231 breast cancer cell metastasis. Cancer Res. 65, 7370–7377 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Shi, Q. et al. Rapid disorganization of mechanically interacting systems of mammary acini. Proc. Natl Acad. Sci. USA 111, 658–663 (2014).

    Article  CAS  PubMed  Google Scholar 

  68. Kim, J. et al. The mechanics and dynamics of cancer cells sensing noisy 3D contact guidance. Proc. Natl Acad. Sci. USA 118, e202478011 (2021).

    Google Scholar 

  69. Kubow, K. E. et al. Mechanical forces regulate the interactions of fibronectin and collagen I in extracellular matrix. Nat. Commun. 6, 8026 (2015).

    Article  CAS  PubMed  Google Scholar 

  70. Dean, Z. S., Elias, P., Jamilpour, N., Utzinger, U. & Wong, P. K. Probing 3D collective cancer invasion using double-stranded locked nucleic acid biosensors. Anal. Chem. 88, 8902–8907 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kim, H. et al. Macrophages-triggered sequential remodeling of endothelium-interstitial matrix to form pre-metastatic niche in microfluidic tumor microenvironment. Adv. Sci. 6, 1900195 (2019).

    Article  CAS  Google Scholar 

  72. Glentis, A. et al. Cancer-associated fibroblasts induce metalloprotease-independent cancer cell invasion of the basement membrane. Nat. Commun. 8, 924 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Caswell, P. T. & Zech, T. Actin-based cell protrusion in a 3D matrix. Trends Cell Biol. 28, 823–834 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Summerbell, E. R. et al. Epigenetically heterogeneous tumor cells direct collective invasion through filopodia-driven fibronectin micropatterning. Sci. Adv. 6, eaaz6197 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kim, J. et al. Stress-induced plasticity of dynamic collagen networks. Nat. Commun. 8, 842 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Han, Y. L. et al. Cell contraction induces long-ranged stress stiffening in the extracellular matrix. Proc. Natl Acad. Sci. USA 115, 4075–4080 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sevenich, L. & Joyce, J. A. Pericellular proteolysis in cancer. Genes Dev. 28, 2331–2347 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Kessenbrock, K., Plaks, V. & Werb, Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52–67 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Gonzalez-Avila, G. et al. Matrix metalloproteinases participation in the metastatic process and their diagnostic and therapeutic applications in cancer. Crit. Rev. Oncol. Hematol. 137, 57–83 (2019).

    Article  PubMed  Google Scholar 

  80. Sternlicht, M. D. & Werb, Z. How matrix metalloproteinases regulate cell behavior. Annu. Rev. Cell Dev. Biol. 17, 463–516 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Murphy, D. A. & Courtneidge, S. A. The ‘ins’ and ‘outs’ of podosomes and invadopodia: characteristics, formation and function. Nat. Rev. Mol. Cell Biol. 12, 413–426 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Li, J. et al. Carcinoma-associated fibroblasts lead the invasion of salivary gland adenoid cystic carcinoma cells by creating an invasive track. PLoS ONE 11, e0150247 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Li, H. et al. Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat. Genet. 49, 708–718 (2017).

    Article  CAS  PubMed  Google Scholar 

  84. Bartoschek, M. et al. Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nat. Commun. 9, 5150 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Sasaki, K. et al. Analysis of cancer-associated fibroblasts and the epithelial–mesenchymal transition in cutaneous basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Hum. Pathol. 79, 1–8 (2018).

    Article  CAS  PubMed  Google Scholar 

  86. Vasiljeva, O. et al. Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer. Cancer Res. 66, 5242–5250 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. 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).

    Article  CAS  PubMed  Google Scholar 

  88. Mierke, C. T. The matrix environmental and cell mechanical properties regulate cell migration and contribute to the invasive phenotype of cancer cells. Rep. Prog. Phys. 82, 064602 (2019).

    Article  CAS  PubMed  Google Scholar 

  89. Friedl, P. & Alexander, S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147, 992–1009 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Wolf, K. & Friedl, P. Extracellular matrix determinants of proteolytic and non-proteolytic cell migration. Trends Cell Biol. 21, 736–744 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Zaman, M. H. et al. Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis. Proc. Natl Acad. Sci. USA 103, 10889–10894 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wisdom, K. M. et al. Matrix mechanical plasticity regulates cancer cell migration through confining microenvironments. Nat. Commun. 9, 4144 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Nam, S., Lee, J., Brownfield, D. G. & Chaudhuri, O. Viscoplasticity enables mechanical remodeling of matrix by cells. Biophys. J. 111, 2296–2308 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Tien, J. et al. Matrix pore size governs escape of human breast cancer cells from a microtumor to an empty cavity. iScience 23, 101673 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Paul, C. D., Mistriotis, P. & Konstantopoulos, K. Cancer cell motility: lessons from migration in confined spaces. Nat. Rev. Cancer 17, 131–140 (2017).

    Article  CAS  PubMed  Google Scholar 

  96. Venturini, V. et al. The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior. Science 370, eaba2644 (2020).

    Article  CAS  PubMed  Google Scholar 

  97. Lomakin, A. J. et al. The nucleus acts as a ruler tailoring cell responses to spatial constraints. Science 370, aba2894 (2020).

    Article  CAS  Google Scholar 

  98. Pandya, P., Orgaz, J. L. & Sanz-Moreno, V. Actomyosin contractility and collective migration: may the force be with you. Curr. Opin. Cell Biol. 48, 87–96 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Khalil, A. A. & de Rooij, J. Cadherin mechanotransduction in leader–follower cell specification during collective migration. Exp. Cell Res. 376, 86–91 (2019).

    Article  CAS  PubMed  Google Scholar 

  100. Hakim, V. & Silberzan, P. Collective cell migration: a physics perspective. Rep. Prog. Phys. 80, 076601 (2017).

    Article  PubMed  CAS  Google Scholar 

  101. Rorth, P. Collective cell migration. Annu. Rev. Cell Dev. Biol. 25, 407–429 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Hamidi, H. & Ivaska, J. Every step of the way: integrins in cancer progression and metastasis. Nat. Rev. Cancer 18, 533–548 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sulzmaier, F. J., Jean, C. & Schlaepfer, D. D. FAK in cancer: mechanistic findings and clinical applications. Nat. Rev. Cancer 14, 598–610 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Gilbert-Ross, M. et al. Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma. JCI Insight 2, e90487 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Rubashkin, M. G. et al. Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate. Cancer Res. 74, 4597–4611 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Haga, R. B. & Ridley, A. J. Rho GTPases: regulation and roles in cancer cell biology. Small GTPases 7, 207–221 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wyckoff, J. B., Pinner, S. E., Gschmeissner, S., Condeelis, J. S. & Sahai, E. ROCK- and myosin-dependent matrix deformation enables protease-independent tumor-cell invasion in vivo. Curr. Biol. 16, 1515–1523 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Holmes, W. R., Park, J., Levchenko, A. & Edelstein-Keshet, L. A mathematical model coupling polarity signaling to cell adhesion explains diverse cell migration patterns. PLoS Comput. Biol. 13, e1005524 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Huang, B. et al. The three-way switch operation of Rac1/RhoA GTPase-based circuit controlling amoeboid-hybrid-mesenchymal transition. Sci. Rep. 4, 6449 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Chrisafis, G. et al. Collective cancer cell invasion requires RNA accumulation at the invasive front. Proc. Natl Acad. Sci. USA 117, 27423–27434 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Moissoglu, K. et al. RNA localization and co-translational interactions control RAB13 GTPase function and cell migration. EMBO J. 39, e104958 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Scott, L. E., Weinberg, S. H. & Lemmon, C. A. Mechanochemical signaling of the extracellular matrix in epithelial–mesenchymal transition. Front. Cell Dev. Biol. 7, 135 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Ladoux, B. & Nicolas, A. Physically based principles of cell adhesion mechanosensitivity in tissues. Rep. Prog. Phys. 75, 116601 (2012).

    Article  PubMed  CAS  Google Scholar 

  115. Padmanaban, V. et al. E-cadherin is required for metastasis in multiple models of breast cancer. Nature 573, 439–444 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Elisha, Y., Kalchenko, V., Kuznetsov, Y. & Geiger, B. Dual role of E-cadherin in the regulation of invasive collective migration of mammary carcinoma cells. Sci. Rep. 8, 4986 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Van den Bossche, J. et al. Alternatively activated macrophages engage in homotypic and heterotypic interactions through IL-4 and polyamine-induced E-cadherin/catenin complexes. Blood 114, 4664–4674 (2009).

    Article  PubMed  CAS  Google Scholar 

  118. Vieira, A. F. & Paredes, J. P-cadherin and the journey to cancer metastasis. Mol. Cancer 14, 178 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Cavallaro, U. N-cadherin as an invasion promoter: a novel target for antitumor therapy? Curr. Opin. Investig. Drugs 5, 1274–1278 (2004).

    CAS  PubMed  Google Scholar 

  120. Ilina, O. et al. Cell–cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion. Nat. Cell Biol. 22, 1103–1115 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Daniel, C. W., Strickland, P. & Friedmann, Y. Expression and functional role of E- and P-cadherins in mouse mammary ductal morphogenesis and growth. Dev. Biol. 169, 511–519 (1995).

    Article  CAS  PubMed  Google Scholar 

  122. Plutoni, C. et al. P-cadherin promotes collective cell migration via a Cdc42-mediated increase in mechanical forces. J. Cell Biol. 212, 199–217 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Apte, R. S., Chen, D. S. & Ferrara, N. VEGF in signaling and disease: beyond discovery and development. Cell 176, 1248–1264 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bachelder, R. E., Wendt, M. A. & Mercurio, A. M. Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4. Cancer Res. 62, 7203–7206 (2002).

    CAS  PubMed  Google Scholar 

  125. Yu, Y. et al. Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-beta signalling. Br. J. Cancer 110, 724–732 (2014).

    Article  CAS  PubMed  Google Scholar 

  126. Aasen, T. et al. Connexins in cancer: bridging the gap to the clinic. Oncogene 38, 4429–4451 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Aasen, T., Mesnil, M., Naus, C. C., Lampe, P. D. & Laird, D. W. Gap junctions and cancer: communicating for 50 years. Nat. Rev. Cancer 16, 775–788 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Wang, H. et al. The osteogenic niche is a calcium reservoir of bone micrometastases and confers unexpected therapeutic vulnerability. Cancer Cell 34, 823–839 e827 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Ito, A. et al. A role for heterologous gap junctions between melanoma and endothelial cells in metastasis. J. Clin. Invest. 105, 1189–1197 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Khalil, A. A. et al. Collective invasion induced by an autocrine purinergic loop through connexin-43 hemichannels. J. Cell Biol. 219, e201911120 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Meurette, O. & Mehlen, P. Notch signaling in the tumor microenvironment. Cancer Cell 34, 536–548 (2018).

    Article  CAS  PubMed  Google Scholar 

  132. Yuan, X. et al. Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett. 369, 20–27 (2015).

    Article  CAS  PubMed  Google Scholar 

  133. Benedito, R. et al. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137, 1124–1135 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. Boareto, M., Jolly, M. K., Ben-Jacob, E. & Onuchic, J. N. Jagged mediates differences in normal and tumor angiogenesis by affecting tip-stalk fate decision. Proc. Natl Acad. Sci. USA 112, E3836–E3844 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wang, S. et al. Intercellular tension negatively regulates angiogenic sprouting of endothelial tip cells via Notch1–Dll4 signaling. Adv. Biosyst. 1, 1600019 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Torab, P. et al. Three-dimensional microtumors for probing heterogeneity of invasive bladder cancer. Anal. Chem. 92, 8768–8775 (2020).

    Article  CAS  PubMed  Google Scholar 

  137. Vilchez, S. et al. Nrf2 regulates collective cancer migration by modulating the hybrid epithelial/mesenchymal phenotype. Preprint at bioRxiv https://doi.org/10.1101/2021.04.21.440858 (2021).

    Article  Google Scholar 

  138. Riahi, R. et al. Notch1–Dll4 signalling and mechanical force regulate leader cell formation during collective cell migration. Nat. Commun. 6, 6556 (2015).

    Article  CAS  PubMed  Google Scholar 

  139. Pignatelli, J. et al. Macrophage-dependent tumor cell transendothelial migration is mediated by Notch1/Mena(INV)-initiated invadopodium formation. Sci. Rep. 6, 37874 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Cheung, K. J. et al. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proc. Natl Acad. Sci. USA 113, E854–E863 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Xu, K. et al. Lunatic fringe deficiency cooperates with the Met/caveolin gene amplicon to induce basal-like breast cancer. Cancer Cell 21, 626–641 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Zhang, Y. et al. Numb and Numbl act to determine mammary myoepithelial cell fate, maintain epithelial identity, and support lactogenesis. FASEB J. 30, 3474–3488 (2016).

    Article  CAS  PubMed  Google Scholar 

  143. Boareto, M. et al. Notch–Jagged signalling can give rise to clusters of cells exhibiting a hybrid epithelial/mesenchymal phenotype. J. R. Soc. Interface 13, 20151106 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Hsu, P. P. & Sabatini, D. M. Cancer cell metabolism: Warburg and beyond. Cell 134, 703–707 (2008).

    Article  CAS  PubMed  Google Scholar 

  145. Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    Article  CAS  PubMed  Google Scholar 

  146. Faubert, B., Solmonson, A. & DeBerardinis, R. J. Metabolic reprogramming and cancer progression. Science 368, eaaw5473 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Commander, R. et al. Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion. Nat. Commun. 11, 1533 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Zhang, J. et al. Energetic regulation of coordinated leader-follower dynamics during collective invasion of breast cancer cells. Proc. Natl Acad. Sci. USA 116, 7867–7872 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Demircioglu, F. et al. Cancer associated fibroblast FAK regulates malignant cell metabolism. Nat. Commun. 11, 1290 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  151. Yang, C. et al. Inducible formation of leader cells driven by CD44 switching gives rise to collective invasion and metastases in luminal breast carcinomas. Oncogene 38, 7113–7132 (2019).

    Article  CAS  PubMed  Google Scholar 

  152. Son, G. M. et al. Comparisons of cancer-associated fibroblasts in the intratumoral stroma and invasive front in colorectal cancer. Medicine 98, e15164 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Pinto, M. L. et al. The two faces of tumor-associated macrophages and their clinical significance in colorectal cancer. Front. Immunol. 10, 1875 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Conklin, M. W. et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am. J. Pathol. 178, 1221–1232 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Evans, R. et al. Integrin-mediated macrophage adhesion promotes lymphovascular dissemination in breast cancer. Cell Rep. 27, 1967–1978.e4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Tanner, K. & Gottesman, M. M. Beyond 3D culture models of cancer. Sci. Transl Med. 7, 283ps289 (2015).

    Article  Google Scholar 

  158. Yang, Y., Jolly, M. K. & Levine, H. Computational modeling of collective cell migration: mechanical and biochemical aspects. Adv. Exp. Med. Biol. 1146, 1–11 (2019).

    Article  CAS  PubMed  Google Scholar 

  159. Frese, K. K. & Tuveson, D. A. Maximizing mouse cancer models. Nat. Rev. Cancer 7, 645–658 (2007).

    Article  CAS  PubMed  Google Scholar 

  160. Wan, Y., Zhu, N., Lu, Y. & Wong, P. K. DNA transformer for visualizing endogenous RNA dynamics in live cells. Anal. Chem. 91, 2626–2633 (2019).

    Article  CAS  PubMed  Google Scholar 

  161. Riahi, R. et al. Mapping photothermally induced gene expression in living cells and tissues by nanorod-locked nucleic acid complexes. ACS Nano 8, 3597–3605 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Tao, S. et al. Oncogenic KRAS confers chemoresistance by upregulating NRF2. Cancer Res. 74, 7430–7441 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Jain, R. K., Munn, L. L. & Fukumura, D. Dissecting tumour pathophysiology using intravital microscopy. Nat. Rev. Cancer 2, 266–276 (2002).

    Article  CAS  PubMed  Google Scholar 

  164. Fischer, K. R. et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527, 472–476 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Zheng, X. F. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by National Science Foundation Center for Theoretical Biological Physics PHY-2019745 (J.N.O., H.L.), CHE-1614101 (J.N.O.), PHY-1605817 (H.L.) and CBET-1802947 (P.K.W.). F.B. is also supported by a grant from the Simons Foundation (594598, QN). J.N.O. is a CPRIT Scholar in Cancer Research. M.K.J. is supported by a Ramanujan Fellowship (SB/S2/RJN-049/2018) awarded by SERB, DST, Government of India.

Author information

Author notes

  1. Federico Bocci

    Present address: NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA

Authors and Affiliations

  1. Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, USA

    Samuel A. Vilchez Mercedes & Pak Kin Wong

  2. Center for Theoretical Biological Physics, Rice University, Houston, TX, USA

    Federico Bocci & José N. Onuchic

  3. Center for Theoretical Biological Physics, Department of Physics, and Department of Bioengineering, Northeastern University, Boston, MA, USA

    Herbert Levine

  4. Department of Physics and Astronomy, Department of Chemistry and Department of Biosciences, Rice University, Houston, TX, USA

    José N. Onuchic

  5. Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India

    Mohit Kumar Jolly

  6. Department of Mechanical Engineering and Department of Surgery, The Pennsylvania State University, University Park, PA, USA

    Pak Kin Wong

Authors
  1. Samuel A. Vilchez Mercedes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Federico Bocci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Herbert Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. José N. Onuchic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohit Kumar Jolly
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pak Kin Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

P.K.W., S.A.V.M. and M.K.J. researched data for the article; all authors contributed to discussion of content, writing, reviewing and editing the manuscript.

Corresponding authors

Correspondence to Herbert Levine, José N. Onuchic, Mohit Kumar Jolly or Pak Kin Wong.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Cancer thanks the anonymous reviewers for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vilchez Mercedes, S.A., Bocci, F., Levine, H. et al. Decoding leader cells in collective cancer invasion. Nat Rev Cancer 21, 592–604 (2021). https://doi.org/10.1038/s41568-021-00376-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-021-00376-8

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer