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.
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Friedl, P., Locker, J., Sahai, E. & Segall, J. E. Classifying collective cancer cell invasion. Nat. Cell Biol. 14, 777–783 (2012).
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).
Friedl, P. et al. Migration of coordinated cell clusters in mesenchymal and epithelial cancer explants in vitro. Cancer Res. 55, 4557–4560 (1995).
Aceto, N. et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158, 1110–1122 (2014).
Nagai, T., Ishikawa, T., Minami, Y. & Nishita, M. Tactics of cancer invasion: solitary and collective invasion. J. Biochem. 167, 347–355 (2020).
Mayor, R. & Etienne-Manneville, S. The front and rear of collective cell migration. Nat. Rev. Mol. Cell Biol. 17, 97–109 (2016).
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).
Zoeller, E. L. et al. Genetic heterogeneity within collective invasion packs drives leader and follower cell phenotypes. J. Cell Sci. 132, jcs231514 (2019).
Westcott, J. M. et al. An epigenetically distinct breast cancer cell subpopulation promotes collective invasion. J. Clin. Invest. 125, 1927–1943 (2015).
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).
Siegel, R. L., Miller, K. D., Fuchs, H. E. & Jemal, A. Cancer statistics, 2021. CA Cancer J. Clin. 71, 7–33 (2021).
Vishwakarma, M., Spatz, J. P. & Das, T. Mechanobiology of leader-follower dynamics in epithelial cell migration. Curr. Opin. Cell Biol. 66, 97–103 (2020).
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).
van Helvert, S., Storm, C. & Friedl, P. Mechanoreciprocity in cell migration. Nat. Cell Biol. 20, 8–20 (2018).
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).
Thiery, J. P. Epithelial–mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442–454 (2002).
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).
Konen, J. et al. Image-guided genomics of phenotypically heterogeneous populations reveals vascular signalling during symbiotic collective cancer invasion. Nat. Commun. 8, 15078 (2017).
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).
Riahi, R. et al. Single cell gene expression analysis in injury-induced collective cell migration. Integr. Biol. 6, 192–202 (2014).
Li, C. F. et al. Snail-induced claudin-11 prompts collective migration for tumour progression. Nat. Cell Biol. 21, 251–262 (2019).
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).
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).
Revenu, C. & Gilmour, D. EMT 2.0: shaping epithelia through collective migration. Curr. Opin. Genet. Dev. 19, 338–342 (2009).
Brabletz, T., Kalluri, R., Nieto, M. A. & Weinberg, R. A. EMT in cancer. Nat. Rev. Cancer 18, 128–134 (2018).
Nieto, M. A., Huang, R. Y., Jackson, R. A. & Thiery, J. P. EMT: 2016. Cell 166, 21–45 (2016).
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).
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).
Zhang, J. et al. TGF-beta-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Sci. Signal. 7, ra91 (2014).
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).
Pastushenko, I. et al. Identification of the tumour transition states occurring during EMT. Nature 556, 463–468 (2018).
Yu, M. et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580–584 (2013).
Quan, Q. H. et al. Cancer stem-like cells with hybrid epithelial/mesenchymal phenotype leading the collective invasion. Cancer Sci. 111, 467–476 (2020).
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).
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).
Choi, W. et al. Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer. Nat. Rev. Urol. 11, 400–410 (2014).
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).
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).
Park, M. et al. Visualizing the contribution of keratin-14+ limbal epithelial precursors in corneal wound healing. Stem Cell Rep. 12, 14–28 (2019).
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).
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).
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).
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).
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).
Sonzogni, O. et al. Reporters to mark and eliminate basal or luminal epithelial cells in culture and in vivo. PLoS Biol. 16, e2004049 (2018).
Dang, T. T. et al. DeltaNp63alpha induces the expression of FAT2 and Slug to promote tumor invasion. Oncotarget 7, 28592–28611 (2016).
Karacosta, L. G. et al. Mapping lung cancer epithelial–mesenchymal transition states and trajectories with single-cell resolution. Nat. Commun. 10, 5587 (2019).
Cook, D. P. & Vanderhyden, B. C. Context specificity of the EMT transcriptional response. Nat. Commun. 11, 2142 (2020).
Yang, J. et al. Guidelines and definitions for research on epithelial–mesenchymal transition. Nat. Rev. Mol. Cell Biol. 21, 341–352 (2020).
desJardins-Park, H. E., Foster, D. S. & Longaker, M. T. Fibroblasts and wound healing: an update. Regen. Med. 13, 491–495 (2018).
Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).
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).
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).
Theret, M., Mounier, R. & Rossi, F. The origins and non-canonical functions of macrophages in development and regeneration. Development 19, dev156000 (2019).
Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).
Zhou, J. et al. Tumor-associated macrophages: recent insights and therapies. Front. Oncol. 10, 188 (2020).
Lin, Y., Xu, J. & Lan, H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J. Hematol. Oncol. 12, 76 (2019).
Sousa, S. et al. Human breast cancer cells educate macrophages toward the M2 activation status. Breast Cancer Res. 17, 101 (2015).
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).
Guiet, R. et al. The process of macrophage migration promotes matrix metalloproteinase-independent invasion by tumor cells. J. Immunol. 187, 3806–3814 (2011).
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).
Haigo, S. L. & Bilder, D. Global tissue revolutions in a morphogenetic movement controlling elongation. Science 331, 1071–1074 (2011).
Attieh, Y. et al. Cancer-associated fibroblasts lead tumor invasion through integrin-beta 3-dependent fibronectin assembly. J. Cell Biol. 216, 3509–3520 (2017).
Erdogan, B. et al. Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. J. Cell Biol. 216, 3799–3816 (2017).
Sangaletti, S. et al. Macrophage-derived SPARC bridges tumor cell-extracellular matrix interactions toward metastasis. Cancer Res. 68, 9050–9059 (2008).
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).
Shi, Q. et al. Rapid disorganization of mechanically interacting systems of mammary acini. Proc. Natl Acad. Sci. USA 111, 658–663 (2014).
Kim, J. et al. The mechanics and dynamics of cancer cells sensing noisy 3D contact guidance. Proc. Natl Acad. Sci. USA 118, e202478011 (2021).
Kubow, K. E. et al. Mechanical forces regulate the interactions of fibronectin and collagen I in extracellular matrix. Nat. Commun. 6, 8026 (2015).
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).
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).
Glentis, A. et al. Cancer-associated fibroblasts induce metalloprotease-independent cancer cell invasion of the basement membrane. Nat. Commun. 8, 924 (2017).
Caswell, P. T. & Zech, T. Actin-based cell protrusion in a 3D matrix. Trends Cell Biol. 28, 823–834 (2018).
Summerbell, E. R. et al. Epigenetically heterogeneous tumor cells direct collective invasion through filopodia-driven fibronectin micropatterning. Sci. Adv. 6, eaaz6197 (2020).
Kim, J. et al. Stress-induced plasticity of dynamic collagen networks. Nat. Commun. 8, 842 (2017).
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).
Sevenich, L. & Joyce, J. A. Pericellular proteolysis in cancer. Genes Dev. 28, 2331–2347 (2014).
Kessenbrock, K., Plaks, V. & Werb, Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52–67 (2010).
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).
Sternlicht, M. D. & Werb, Z. How matrix metalloproteinases regulate cell behavior. Annu. Rev. Cell Dev. Biol. 17, 463–516 (2001).
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).
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).
Li, H. et al. Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat. Genet. 49, 708–718 (2017).
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).
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).
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).
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).
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).
Friedl, P. & Alexander, S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147, 992–1009 (2011).
Wolf, K. & Friedl, P. Extracellular matrix determinants of proteolytic and non-proteolytic cell migration. Trends Cell Biol. 21, 736–744 (2011).
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).
Wisdom, K. M. et al. Matrix mechanical plasticity regulates cancer cell migration through confining microenvironments. Nat. Commun. 9, 4144 (2018).
Nam, S., Lee, J., Brownfield, D. G. & Chaudhuri, O. Viscoplasticity enables mechanical remodeling of matrix by cells. Biophys. J. 111, 2296–2308 (2016).
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).
Paul, C. D., Mistriotis, P. & Konstantopoulos, K. Cancer cell motility: lessons from migration in confined spaces. Nat. Rev. Cancer 17, 131–140 (2017).
Venturini, V. et al. The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior. Science 370, eaba2644 (2020).
Lomakin, A. J. et al. The nucleus acts as a ruler tailoring cell responses to spatial constraints. Science 370, aba2894 (2020).
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).
Khalil, A. A. & de Rooij, J. Cadherin mechanotransduction in leader–follower cell specification during collective migration. Exp. Cell Res. 376, 86–91 (2019).
Hakim, V. & Silberzan, P. Collective cell migration: a physics perspective. Rep. Prog. Phys. 80, 076601 (2017).
Rorth, P. Collective cell migration. Annu. Rev. Cell Dev. Biol. 25, 407–429 (2009).
Hamidi, H. & Ivaska, J. Every step of the way: integrins in cancer progression and metastasis. Nat. Rev. Cancer 18, 533–548 (2018).
Sulzmaier, F. J., Jean, C. & Schlaepfer, D. D. FAK in cancer: mechanistic findings and clinical applications. Nat. Rev. Cancer 14, 598–610 (2014).
Gilbert-Ross, M. et al. Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma. JCI Insight 2, e90487 (2017).
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).
Haga, R. B. & Ridley, A. J. Rho GTPases: regulation and roles in cancer cell biology. Small GTPases 7, 207–221 (2016).
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).
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).
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).
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).
Chrisafis, G. et al. Collective cancer cell invasion requires RNA accumulation at the invasive front. Proc. Natl Acad. Sci. USA 117, 27423–27434 (2020).
Moissoglu, K. et al. RNA localization and co-translational interactions control RAB13 GTPase function and cell migration. EMBO J. 39, e104958 (2020).
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).
Ladoux, B. & Nicolas, A. Physically based principles of cell adhesion mechanosensitivity in tissues. Rep. Prog. Phys. 75, 116601 (2012).
Padmanaban, V. et al. E-cadherin is required for metastasis in multiple models of breast cancer. Nature 573, 439–444 (2019).
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).
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).
Vieira, A. F. & Paredes, J. P-cadherin and the journey to cancer metastasis. Mol. Cancer 14, 178 (2015).
Cavallaro, U. N-cadherin as an invasion promoter: a novel target for antitumor therapy? Curr. Opin. Investig. Drugs 5, 1274–1278 (2004).
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).
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).
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).
Apte, R. S., Chen, D. S. & Ferrara, N. VEGF in signaling and disease: beyond discovery and development. Cell 176, 1248–1264 (2019).
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).
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).
Aasen, T. et al. Connexins in cancer: bridging the gap to the clinic. Oncogene 38, 4429–4451 (2019).
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).
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).
Ito, A. et al. A role for heterologous gap junctions between melanoma and endothelial cells in metastasis. J. Clin. Invest. 105, 1189–1197 (2000).
Khalil, A. A. et al. Collective invasion induced by an autocrine purinergic loop through connexin-43 hemichannels. J. Cell Biol. 219, e201911120 (2020).
Meurette, O. & Mehlen, P. Notch signaling in the tumor microenvironment. Cancer Cell 34, 536–548 (2018).
Yuan, X. et al. Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett. 369, 20–27 (2015).
Benedito, R. et al. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137, 1124–1135 (2009).
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).
Wang, S. et al. Intercellular tension negatively regulates angiogenic sprouting of endothelial tip cells via Notch1–Dll4 signaling. Adv. Biosyst. 1, 1600019 (2017).
Torab, P. et al. Three-dimensional microtumors for probing heterogeneity of invasive bladder cancer. Anal. Chem. 92, 8768–8775 (2020).
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).
Riahi, R. et al. Notch1–Dll4 signalling and mechanical force regulate leader cell formation during collective cell migration. Nat. Commun. 6, 6556 (2015).
Pignatelli, J. et al. Macrophage-dependent tumor cell transendothelial migration is mediated by Notch1/Mena(INV)-initiated invadopodium formation. Sci. Rep. 6, 37874 (2016).
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).
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).
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).
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).
Hsu, P. P. & Sabatini, D. M. Cancer cell metabolism: Warburg and beyond. Cell 134, 703–707 (2008).
Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).
Faubert, B., Solmonson, A. & DeBerardinis, R. J. Metabolic reprogramming and cancer progression. Science 368, eaaw5473 (2020).
Commander, R. et al. Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion. Nat. Commun. 11, 1533 (2020).
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).
Demircioglu, F. et al. Cancer associated fibroblast FAK regulates malignant cell metabolism. Nat. Commun. 11, 1290 (2020).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
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).
Son, G. M. et al. Comparisons of cancer-associated fibroblasts in the intratumoral stroma and invasive front in colorectal cancer. Medicine 98, e15164 (2019).
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).
Pinto, M. L. et al. The two faces of tumor-associated macrophages and their clinical significance in colorectal cancer. Front. Immunol. 10, 1875 (2019).
Conklin, M. W. et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am. J. Pathol. 178, 1221–1232 (2011).
Evans, R. et al. Integrin-mediated macrophage adhesion promotes lymphovascular dissemination in breast cancer. Cell Rep. 27, 1967–1978.e4 (2019).
Tanner, K. & Gottesman, M. M. Beyond 3D culture models of cancer. Sci. Transl Med. 7, 283ps289 (2015).
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).
Frese, K. K. & Tuveson, D. A. Maximizing mouse cancer models. Nat. Rev. Cancer 7, 645–658 (2007).
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).
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).
Tao, S. et al. Oncogenic KRAS confers chemoresistance by upregulating NRF2. Cancer Res. 74, 7430–7441 (2014).
Jain, R. K., Munn, L. L. & Fukumura, D. Dissecting tumour pathophysiology using intravital microscopy. Nat. Rev. Cancer 2, 266–276 (2002).
Fischer, K. R. et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527, 472–476 (2015).
Zheng, X. F. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015).
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.
The authors declare no competing interests.
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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