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Collective Cellular Phase Transitions in Cancer

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Engineering and Physical Approaches to Cancer

Part of the book series: Current Cancer Research ((CUCR))

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Abstract

The growth and metastasis of tumors are increasingly recognized to be an inherently collective, multiscale problem, wherein understanding at the genetic and molecular level is necessary but is not sufficient; the mechanical response of cells must also be accounted for to understand collective behavior in cancer. Like glassy, granular, and colloidal materials, cells exist in a fundamentally crowded and disordered environment and are capable of undergoing collective phase transitions between states resembling the material phases of solid, liquid, and gas. By mapping concepts from material science to cell motion, it becomes possible to better predict and understand how macroscopic properties of the cellular system – fluidity and rigidity – emerge from physical cellular-scale interactions. These cellular interactions, though enormously complex and variable from a biological standpoint, can be abstracted to generalized state variables, including density, cell shape constraints, and fluctuations, which allow phase diagrams to be constructed to aid in predicting behavior. In this chapter, we review both experimental evidence and theoretical frameworks toward understanding multicellular collectives as material systems, exploring both the power and the limitations of comparisons between biological and non-living soft matter systems. We conclude with how these lessons are being applied to develop a more holistic understanding of how physical constraints affect collective migration and invasion in cancer.

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References

  1. Dagogo-Jack I, Shaw AT (2018) Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol 15:81–94

    Article  CAS  PubMed  Google Scholar 

  2. Byun S et al (2013) Characterizing deformability and surface friction of cancer cells. Proc Natl Acad Sci 110:7580–7585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vogelstein B et al (2013) Cancer genome landscapes. Science 339:1546–1558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. McGranahan N, Swanton C (2015) Biological and therapeutic impact of Intratumor heterogeneity in cancer evolution. Cancer Cell 27:15–26

    Article  CAS  PubMed  Google Scholar 

  5. Anderson NM, Simon MC (2020) The tumor microenvironment. Curr Biol 30:R921–R925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sadati M, Taheri Qazvini N, Krishnan R, Park CY, Fredberg JJ (2013) Collective migration and cell jamming. Differentiation 86:121–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pegoraro AF, Fredberg JJ, Park J-A (2016) Problems in biology with many scales of length: cell-cell adhesion and cell jamming in collective cellular migration. Exp Cell Res 343:54–59

    Article  CAS  PubMed  Google Scholar 

  8. Lenne P-F, Trivedi V (2022) Sculpting tissues by phase transitions. Nat Commun 13:664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Blauth E, Kubitschke H, Gottheil P, Grosser S, Käs JA (2021) Jamming in embryogenesis and cancer progression. Front Phys 9:666709

    Article  Google Scholar 

  10. Schoenholz SS, Cubuk ED, Sussman DM, Kaxiras E, Liu AJ (2016) A structural approach to relaxation in glassy liquids. Nat Phys 12:469–471

    Article  CAS  Google Scholar 

  11. Cubuk ED et al (2017) Structure-property relationships from universal signatures of plasticity in disordered solids. Science 358:1033–1037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schoenholz SS, Cubuk ED, Kaxiras E, Liu AJ (2017) Relationship between local structure and relaxation in out-of-equilibrium glassy systems. Proc Natl Acad Sci 114:263–267

    Article  CAS  PubMed  Google Scholar 

  13. Tah I, Sharp TA, Liu AJ, Sussman DM (2021) Quantifying the link between local structure and cellular rearrangements using information in models of biological tissues. Soft Matter 17:10242–10253

    Article  CAS  PubMed  Google Scholar 

  14. Ellis GFR, Kopel J (2019) The dynamical emergence of biology from physics: branching causation via biomolecules. Front Physiol 9:1966

    Article  PubMed  PubMed Central  Google Scholar 

  15. Anderson PW (1972) More Is Different. Science 177:393–396

    Article  CAS  PubMed  Google Scholar 

  16. Strogatz S et al (2022) Fifty years of ‘More is different’. Nat Rev Phys 4:508–510

    Article  Google Scholar 

  17. Zaidel-Bar R (2013) Cadherin adhesome at a glance. J Cell Sci 126:373–378

    Article  CAS  PubMed  Google Scholar 

  18. Janiszewska M, Primi MC, Izard T (2020) Cell adhesion in cancer: beyond the migration of single cells. J Biol Chem 295:2495–2505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Castor LN (1968) Contact regulation of cell division in an epithelial-like cell line. J Cell Physiol 72:161–172

    Article  CAS  PubMed  Google Scholar 

  20. Abercrombie M (1970) Contact inhibition in tissue culture. In Vitro 6:128–142

    Article  CAS  PubMed  Google Scholar 

  21. Martz E, Steinberg MS (1972) The role of cell-cell contact in “contact” inhibition of cell division: a review and new evidence. J Cell Physiol 79:189–210

    Article  CAS  PubMed  Google Scholar 

  22. Huttenlocher A et al (1998) Integrin and cadherin synergy regulates contact inhibition of migration and motile activity. J Cell Biol 141:515–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Halbleib JM, Nelson WJ (2006) Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes Dev 20:3199–3214

    Article  CAS  PubMed  Google Scholar 

  24. Takai Y, Miyoshi J, Ikeda W, Ogita H (2008) Nectins and nectin-like molecules: roles in contact inhibition of cell movement and proliferation. Nat Rev Mol Cell Biol 9:603–615

    Article  CAS  PubMed  Google Scholar 

  25. Zeng Q, Hong W (2008) The emerging role of the hippo pathway in cell contact inhibition, organ size control, and cancer development in mammals. Cancer Cell 13:188–192

    Article  CAS  PubMed  Google Scholar 

  26. Farhadifar R, Röper J-C, Aigouy B, Eaton S, Jülicher F (2007) The influence of cell mechanics, cell-cell interactions, and proliferation on epithelial packing. Curr Biol 17:2095–2104

    Article  CAS  PubMed  Google Scholar 

  27. Douezan S et al (2011) Spreading dynamics and wetting transition of cellular aggregates. Proc Natl Acad Sci U S A 108:7315–7320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gonzalez-Rodriguez D, Guevorkian K, Douezan S, Brochard-Wyart F (2012) Soft matter models of developing tissues and tumors. Science 338:910–917

    Article  CAS  PubMed  Google Scholar 

  29. Behringer RP, Chakraborty B (2019) The physics of jamming for granular materials: a review. Rep Prog Phys 82:012601

    Article  CAS  PubMed  Google Scholar 

  30. Trappe V, Prasad V, Cipelletti L, Segre PN, Weitz DA (2001) Jamming phase diagram for attractive particles. Nature 411:772–775

    Article  CAS  PubMed  Google Scholar 

  31. Liu AJ, Nagel SR (1998) Jamming is not just cool any more. Nature 396:21–22

    Article  CAS  Google Scholar 

  32. Liu AJ, Nagel SR (2010) The jamming transition and the marginally jammed solid. Annu Rev Cond Matter Phys 1:347–369

    Article  Google Scholar 

  33. Angelini TE et al (2011) Glass-like dynamics of collective cell migration. Proc Natl Acad Sci 108:4714–4719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Garcia S et al (2015) Physics of active jamming during collective cellular motion in a monolayer. Proc Natl Acad Sci 112:15314–15319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Castro MG, Leggett SE, Wong IY (2016) Clustering and jamming in epithelial–mesenchymal co-cultures. Soft Matter 12:8327–8337

    Article  CAS  PubMed Central  Google Scholar 

  36. Saraswathibhatla A, Notbohm J (2020) Tractions and stress fibers control cell shape and rearrangements in collective cell migration. Phys Rev X 10:011016

    CAS  Google Scholar 

  37. Vishwakarma M, Thurakkal B, Spatz JP, Das T (2020) Dynamic heterogeneity influences the leader–follower dynamics during epithelial wound closure. Philos Trans R Soc Lond B Biol Sci 375:20190391

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kim JH et al (2020) Unjamming and collective migration in MCF10A breast cancer cell lines. Biochem Biophys Res Commun 521:706–715

    Article  CAS  PubMed  Google Scholar 

  39. Mongera A et al (2018) A fluid-to-solid jamming transition underlies vertebrate body axis elongation. Nature 561:401–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Petridou NI, Corominas-Murtra B, Heisenberg C-P, Hannezo E (2021) Rigidity percolation uncovers a structural basis for embryonic tissue phase transitions. Cell 184:1914–1928.e19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bi D, Yang X, Marchetti MC, Manning ML (2016) Motility-driven glass and jamming transitions in biological tissues. Phys Rev X 6:021011

    PubMed  PubMed Central  Google Scholar 

  42. Lawson-Keister E, Manning ML (2021) Jamming and arrest of cell motion in biological tissues. Curr Opin Cell Biol 72:146–155

    Article  CAS  PubMed  Google Scholar 

  43. Yang H et al (2021) Configurational fingerprints of multicellular living systems. Proc Natl Acad Sci 118:e2109168118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Devany J, Sussman DM, Yamamoto T, Manning ML, Gardel ML (2021) Cell cycle–dependent active stress drives epithelia remodeling. Proc Natl Acad Sci 118:e1917853118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Park J-A et al (2015) Unjamming and cell shape in the asthmatic airway epithelium. Nat Mater 14:1040–1048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nnetu KD, Knorr M, Pawlizak S, Fuhs T, Käs JA (2013) Slow and anomalous dynamics of an MCF-10A epithelial cell monolayer. Soft Matter 9:9335–9341

    Article  CAS  Google Scholar 

  47. Hannezo E, Heisenberg C-P (2019) Mechanochemical feedback loops in development and disease. Cell 178:12–25

    Article  CAS  PubMed  Google Scholar 

  48. Mattsson J et al (2009) Soft colloids make strong glasses. Nature 462:83–86

    Article  CAS  PubMed  Google Scholar 

  49. Viljoen A et al (2021) Force spectroscopy of single cells using atomic force microscopy. Nat Rev Methods Primer 1:1–24

    Article  Google Scholar 

  50. Zhang H, Liu K-K (2008) Optical tweezers for single cells. J R Soc Interface. https://doi.org/10.1098/rsif.2008.0052

  51. Wang N, Butler JP, Ingber DE (1993) Mechanotransduction across the cell surface and through the cytoskeleton. Science 260:1124–1127

    Article  CAS  PubMed  Google Scholar 

  52. Puig-De-Morales M et al (2001) Measurement of cell microrheology by magnetic twisting cytometry with frequency domain demodulation. J Appl Physiol 91:1152–1159

    Article  CAS  PubMed  Google Scholar 

  53. Prevedel R, Diz-Muñoz A, Ruocco G, Antonacci G (2019) Brillouin microscopy: an emerging tool for mechanobiology. Nat Methods 16:969–977

    Article  CAS  PubMed  Google Scholar 

  54. Fujii Y et al (2019) Spontaneous spatial correlation of elastic modulus in jammed epithelial monolayers observed by AFM. Biophys J 116:1152–1158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Efremov YM et al (2021) Mechanical properties of cell sheets and spheroids: the link between single cells and complex tissues. Biophys Rev 13:541–561

    Article  PubMed  PubMed Central  Google Scholar 

  56. Petridou NI, Grigolon S, Salbreux G, Hannezo E, Heisenberg C-P (2019) Fluidization-mediated tissue spreading by mitotic cell rounding and non-canonical Wnt signalling. Nat Cell Biol 21:169–178

    Article  CAS  PubMed  Google Scholar 

  57. Hochmuth RM (2000) Micropipette aspiration of living cells. J Biomech 33:15–22

    Article  CAS  PubMed  Google Scholar 

  58. Aoki T, Ohashi T, Matsumoto T, Sato M (1997) The pipette aspiration applied to the local stiffness measurement of soft tissues. Ann Biomed Eng 25:581–587

    Article  CAS  PubMed  Google Scholar 

  59. Serwane F et al (2017) In vivo quantification of spatially varying mechanical properties in developing tissues. Nat Methods 14:181–186

    Article  CAS  PubMed  Google Scholar 

  60. Berthier L, Flenner E, Szamel G (2019) Glassy dynamics in dense systems of active particles. J Chem Phys 150:200901

    Article  PubMed  Google Scholar 

  61. Berthier L (2011) Dynamic heterogeneity in amorphous materials. Physics 4:42

    Article  Google Scholar 

  62. Lu (陸述義) PJ, Weitz DA (2013) Colloidal particles: crystals, glasses, and gels. Annu Rev Condens Matter Phys 4:217–233

    Article  Google Scholar 

  63. Trepat X et al (2009) Physical forces during collective cell migration. Nat Phys 5:426–430

    Article  CAS  Google Scholar 

  64. Tambe DT et al (2011) Collective cell guidance by cooperative intercellular forces. Nat Mater 10:469–475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Garrahan JP (2011) Dynamic heterogeneity comes to life. Proc Natl Acad Sci 108:4701–4702

    Article  CAS  PubMed Central  Google Scholar 

  66. Bi D, Lopez JH, Schwarz JM, Manning ML (2015) A density-independent rigidity transition in biological tissues. Nat Phys 11:1074–1079

    Article  CAS  Google Scholar 

  67. Bi D, Lopez JH, Schwarz JM, Manning ML (2014) Energy barriers and cell migration in densely packed tissues. Soft Matter 10:1885–1890

    Article  CAS  PubMed  Google Scholar 

  68. Li X, Das A, Bi D (2019) Mechanical heterogeneity in tissues promotes rigidity and controls cellular invasion. Phys Rev Lett 123:058101

    Article  CAS  PubMed  Google Scholar 

  69. Atia L et al (2018) Geometric constraints during epithelial jamming. Nat Phys 14:613–620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mitchel JA et al (2020) In primary airway epithelial cells, the unjamming transition is distinct from the epithelial-to-mesenchymal transition. Nat Commun 11:5053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Han YL et al (2020) Cell swelling, softening and invasion in a three-dimensional breast cancer model. Nat Phys 16:101–108

    Article  CAS  PubMed  Google Scholar 

  72. Kang W et al (2021) A novel jamming phase diagram links tumor invasion to non-equilibrium phase separation. iScience 24:103252

    Article  PubMed  PubMed Central  Google Scholar 

  73. Henkes S, Fily Y, Marchetti MC (2011) Active jamming: self-propelled soft particles at high density. Phys Rev E 84:040301

    Article  Google Scholar 

  74. Roycroft A et al (2018) Redistribution of adhesive forces through Src/FAK drives contact inhibition of locomotion in neural crest. Dev Cell 45:565–579.e3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mayor R, Carmona-Fontaine C (2010) Keeping in touch with contact inhibition of locomotion. Trends Cell Biol 20:319–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Roycroft A, Mayor R (2016) Molecular basis of contact inhibition of locomotion. Cell Mol Life Sci 73:1119–1130

    Article  CAS  PubMed  Google Scholar 

  77. Carmona-Fontaine C et al (2008) Contact inhibition of locomotion in vivo controls neural crest directional migration. Nature 456:957–961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Khataee H, Czirok A, Neufeld Z (2021) Contact inhibition of locomotion generates collective cell migration without chemoattractants in an open domain. Phys Rev E 104:014405

    Article  CAS  PubMed  Google Scholar 

  79. Fagotto F (2014) The cellular basis of tissue separation. Development 141:3303–3318

    Article  CAS  PubMed  Google Scholar 

  80. Shellard A, Mayor R (2019) Supracellular migration – beyond collective cell migration. J Cell Sci 132:jcs226142

    Article  CAS  PubMed  Google Scholar 

  81. Haeger A, Krause M, Wolf K, Friedl P (2014) Cell jamming: collective invasion of mesenchymal tumor cells imposed by tissue confinement. Biochim Biophys Acta BBA Gen Subj 1840:2386–2395

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Szabó A et al (2016) In vivo confinement promotes collective migration of neural crest cells. J Cell Biol 213:543–555

    Article  PubMed  PubMed Central  Google Scholar 

  84. Xi W, Sonam S, Beng Saw T, Ladoux B, Teck Lim C (2017) Emergent patterns of collective cell migration under tubular confinement. Nat Commun 8:1517

    Article  PubMed  PubMed Central  Google Scholar 

  85. Angelini TE, Hannezo E, Trepat X, Fredberg JJ, Weitz DA (2010) Cell migration driven by cooperative substrate deformation patterns. Phys Rev Lett 104:168104

    Article  PubMed  PubMed Central  Google Scholar 

  86. Nehls S, Nöding H, Karsch S, Ries F, Janshoff A (2019) Stiffness of MDCK II cells depends on confluency and cell size. Biophys J 116:2204–2211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Firmino J, Rocancourt D, Saadaoui M, Moreau C, Gros J (2016) Cell division drives epithelial cell rearrangements during gastrulation in Chick. Dev Cell 36:249–261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ranft J et al (2010) Fluidization of tissues by cell division and apoptosis. Proc Natl Acad Sci 107:20863–20868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Rosenblatt J, Raff MC, Cramer LP (2001) An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism. Curr Biol 11:1847–1857

    Article  CAS  PubMed  Google Scholar 

  90. Marinari E et al (2012) Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding. Nature 484:542–545

    Article  CAS  PubMed  Google Scholar 

  91. Moitrier S et al (2019) Local light-activation of the Src oncoprotein in an epithelial monolayer promotes collective extrusion. Commun Phys 2:1–11

    Article  CAS  Google Scholar 

  92. Yuan Y et al (2022) Recovery of structural integrity of epithelial monolayer in response to massive apoptosis-induced defects. 2022.08.08.503238 Preprint at https://doi.org/10.1101/2022.08.08.503238

  93. Ruth ES (1911) Cicatrization of wounds in vitro. J Exp Med 13:422–424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  95. Krause M, Gautreau A (2014) Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. Nat Rev Mol Cell Biol 15:577–590

    Article  CAS  PubMed  Google Scholar 

  96. Enyedi B, Niethammer P (2015) Mechanisms of epithelial wound detection. Trends Cell Biol 25:398–407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Klarlund JK, Block ER (2011) Free edges in epithelia as cues for motility. Cell Adhes Migr 5:106–110

    Article  Google Scholar 

  98. Serra-Picamal X et al (2012) Mechanical waves during tissue expansion. Nat Phys 8:628–634

    Article  CAS  Google Scholar 

  99. Poujade M et al (2007) Collective migration of an epithelial monolayer in response to a model wound. Proc Natl Acad Sci 104:15988–15993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Rausch S et al (2013) Polarizing cytoskeletal tension to induce leader cell formation during collective cell migration. Biointerphases 8:32

    Article  PubMed  Google Scholar 

  101. Vishwakarma M et al (2018) Mechanical interactions among followers determine the emergence of leaders in migrating epithelial cell collectives. Nat Commun 9:3469

    Article  PubMed  PubMed Central  Google Scholar 

  102. Tlili S et al (2018) Collective cell migration without proliferation: density determines cell velocity and wave velocity. R Soc Open Sci 5:172421

    Article  PubMed  PubMed Central  Google Scholar 

  103. Hino N et al (2020) ERK-mediated Mechanochemical waves direct collective cell polarization. Dev Cell 53:646–660.e8

    Article  CAS  PubMed  Google Scholar 

  104. Boocock D, Hino N, Ruzickova N, Hirashima T, Hannezo E (2021) Theory of mechanochemical patterning and optimal migration in cell monolayers. Nat Phys 17:267–274

    Article  CAS  Google Scholar 

  105. Nnetu KD, Knorr M, Käs J, Zink M (2012) The impact of jamming on boundaries of collectively moving weak-interacting cells. New J Phys 14:115012

    Article  Google Scholar 

  106. DeCamp SJ et al (2020) Epithelial layer unjamming shifts energy metabolism toward glycolysis. Sci Rep 10:18302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Nnetu KD, Knorr M, Strehle D, Zink M, Käs JA (2012) Directed persistent motion maintains sheet integrity during multi-cellular spreading and migration. Soft Matter 8:6913–6921

    Article  CAS  Google Scholar 

  108. Chepizhko O et al (2018) From jamming to collective cell migration through a boundary induced transition. Soft Matter 14:3774–3782

    Article  CAS  PubMed  Google Scholar 

  109. Rodríguez-Franco P et al (2017) Long-lived force patterns and deformation waves at repulsive epithelial boundaries. Nat Mater 16:1029–1037

    Article  PubMed  PubMed Central  Google Scholar 

  110. Heinrich MA, Alert R, Wolf AE, Košmrlj A, Cohen DJ (2022) Self-assembly of tessellated tissue sheets by expansion and collision. Nat Commun 13:4026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Heine P, Lippoldt J, Reddy GA, Katira P, Käs JA (2021) Anomalous cell sorting behavior in mixed monolayers discloses hidden system complexities. New J Phys 23:043034

    Article  Google Scholar 

  112. Fernandez-Gonzalez R, Zallen JA (2012) Feeling the squeeze: live-cell extrusion limits cell density in epithelia. Cell 149:965–967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Eisenhoffer GT et al (2012) Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia. Nature 484:546–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Lohani S et al (2022) A novel role for PRL in regulating epithelial cell density by inducing apoptosis at confluence. J Cell Sci 135:jcs258550

    Article  CAS  PubMed  Google Scholar 

  115. Halter M, Elliott JT, Hubbard JB, Tona A, Plant AL (2009) Cell volume distributions reveal cell growth rates and division times. J Theor Biol 257:124–130

    Article  PubMed  Google Scholar 

  116. Puliafito A, Primo L, Celani A (2017) Cell-size distribution in epithelial tissue formation and homeostasis. J R Soc Interface 14:20170032

    Article  PubMed  PubMed Central  Google Scholar 

  117. Puliafito A et al (2012) Collective and single cell behavior in epithelial contact inhibition. Proc Natl Acad Sci U S A 109:739–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Tzur A, Kafri R, LeBleu VS, Lahav G, Kirschner MW (2009) Cell growth and size homeostasis in proliferating animal cells. Science 325:167–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Gudipaty SA et al (2017) Mechanical stretch triggers rapid epithelial cell division through Piezo1. Nature 543:118–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Walck-Shannon E, Hardin J (2014) Cell intercalation from top to bottom. Nat Rev Mol Cell Biol 15:34–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Malinverno C et al (2017) Endocytic reawakening of motility in jammed epithelia. Nat Mater 16:587–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Bertet C, Sulak L, Lecuit T (2004) Myosin-dependent junction remodelling controls planar cell intercalation and axis elongation. Nature 429:667–671

    Article  CAS  PubMed  Google Scholar 

  123. Otani T, Ichii T, Aono S, Takeichi M (2006) Cdc42 GEF Tuba regulates the junctional configuration of simple epithelial cells. J Cell Biol 175:135–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Franke JD, Montague RA, Kiehart DP (2005) Nonmuscle Myosin II generates forces that transmit tension and drive contraction in multiple tissues during dorsal closure. Curr Biol 15:2208–2221

    Article  CAS  PubMed  Google Scholar 

  125. O’Sullivan MJ et al (2020) Irradiation induces epithelial cell unjamming. Front Cell Dev Biol 8:21

    Article  PubMed  PubMed Central  Google Scholar 

  126. Phung T-KN, Mitchel JA, O’Sullivan MJ, Park J-A (2022) In airway epithelium, basal stem cells and their stress fibers remodel during the unjamming transition. 2022.08.18.504453 Preprint at https://doi.org/10.1101/2022.08.18.504453

  127. Saraswathibhatla A, Henkes S, Galles EE, Sknepnek R, Notbohm J (2021) Coordinated tractions increase the size of a collectively moving pack in a cell monolayer. Extreme Mech Lett 48:101438

    Article  Google Scholar 

  128. Stancil IT et al (2022) Interleukin-6–dependent epithelial fluidization initiates fibrotic lung remodeling. Sci Transl Med 14:eabo5254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Stancil IT et al (2021) Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional. Nat Commun 12:4566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Palamidessi A et al (2019) Unjamming overcomes kinetic and proliferation arrest in terminally differentiated cells and promotes collective motility of carcinoma. Nat Mater 18:1252–1263

    Article  CAS  PubMed  Google Scholar 

  131. Frittoli E et al (2022) Tissue fluidification promotes a cGAS/STING-mediated cytosolic DNA response in invasive breast cancer. Nature Mat. https://doi.org/10.1038/s41563-022-01431-x

  132. Aoki K et al (2017) Propagating wave of ERK activation orients collective cell migration. Dev Cell 43:305–317.e5

    Article  CAS  PubMed  Google Scholar 

  133. Matsubayashi Y, Ebisuya M, Honjoh S, Nishida E (2004) ERK activation propagates in epithelial cell sheets and regulates their migration during wound healing. Curr Biol 14:731–735

    Article  CAS  PubMed  Google Scholar 

  134. Moshe M, Bowick MJ, Marchetti MC (2018) Geometric frustration and solid-solid transitions in model 2D tissue. Phys Rev Lett 120:268105

    Article  CAS  PubMed  Google Scholar 

  135. Shellard A, Mayor R (2020) Rules of collective migration: from the wildebeest to the neural crest. Philos Trans R Soc Lond B Biol Sci 375:20190387

    Article  PubMed  PubMed Central  Google Scholar 

  136. Vicsek T, Zafeiris A (2012) Collective motion. Phys Rep 517:71–140

    Article  Google Scholar 

  137. Szabó B et al (2006) Phase transition in the collective migration of tissue cells: experiment and model. Phys Rev E 74:061908

    Article  Google Scholar 

  138. Lin S-Z, Ye S, Xu G-K, Li B, Feng X-Q (2018) Dynamic migration Modes of collective cells. Biophys J 115:1826–1835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Vicsek T, Czirók A, Ben-Jacob E, Cohen I, Shochet O (1995) Novel type of phase transition in a system of self-driven particles. Phys Rev Lett 75:1226–1229

    Article  CAS  PubMed  Google Scholar 

  140. Lacayo CI et al (2007) Emergence of large-scale cell morphology and movement from local actin filament growth dynamics. PLoS Biol 5:e233

    Article  PubMed  PubMed Central  Google Scholar 

  141. Toner J, Tu Y (1995) Long-range order in a two-dimensional dynamical XY model: how birds Fly together. Phys Rev Lett 75:4326–4329

    Article  CAS  PubMed  Google Scholar 

  142. Toner J, Tu Y (1998) Flocks, herds, and schools: a quantitative theory of flocking. Phys Rev E 58:4828–4858

    Article  CAS  Google Scholar 

  143. Toner J, Tu Y, Ramaswamy S (2005) Hydrodynamics and phases of flocks. Ann Phys 318:170–244

    Article  CAS  Google Scholar 

  144. Giavazzi F et al (2018) Flocking transitions in confluent tissues. Soft Matter 14:3471–3477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Shankar S, Souslov A, Bowick MJ, Marchetti MC, Vitelli V (2022) Topological active matter. Nat Rev Phys 4:380–398

    Article  Google Scholar 

  146. Duclut C, Paijmans J, Inamdar MM, Modes CD, Jülicher F (2022) Active T1 transitions in cellular networks. Eur Phys J E 45:29

    Article  CAS  PubMed  Google Scholar 

  147. Clark AG, Vignjevic DM (2015) Modes of cancer cell invasion and the role of the microenvironment. Curr Opin Cell Biol 36:13–22

    Article  CAS  PubMed  Google Scholar 

  148. Friedl P, Gilmour D (2009) Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 10:445–457

    Article  CAS  PubMed  Google Scholar 

  149. Reymond N, d’Água BB, Ridley AJ (2013) Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13:858–870

    Article  CAS  PubMed  Google Scholar 

  150. Friedl P (2004) Prespecification and plasticity: shifting mechanisms of cell migration. Curr Opin Cell Biol 16:14–23

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  152. Vignjevic D et al (2007) Fascin, a novel target of β-catenin-TCF signaling, is expressed at the invasive front of human colon cancer. Cancer Res 67:6844–6853

    Article  CAS  PubMed  Google Scholar 

  153. Tarin D (2005) The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 65:5996–6001

    Article  CAS  PubMed  Google Scholar 

  154. Wang X, Enomoto A, Asai N, Kato T, Takahashi M (2016) Collective invasion of cancer: perspectives from pathology and development. Pathol Int 66:183–192

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  156. Cheung KJ, Gabrielson E, Werb Z, Ewald AJ (2013) Collective invasion in breast cancer requires a conserved basal epithelial program. Cell 155:1639–1651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Cheung KJ, Ewald AJ (2016) A collective route to metastasis: seeding by tumor cell clusters. Science 352:167–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Amintas S et al (2020) Circulating tumor cell clusters: united we stand divided we fall. Int J Mol Sci 21:2653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Cheung KJ et al (2016) Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proc Natl Acad Sci 113:E854–E863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Maddipati R, Stanger BZ (2015) Pancreatic cancer metastases harbor evidence of polyclonality. Cancer Discov 5:1086–1097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Gunti S, Hoke ATK, Vu KP, London NR (2021) Organoid and spheroid tumor models: techniques and applications. Cancers 13:874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Douezan S, Dumond J, Brochard-Wyart F (2012) Wetting transitions of cellular aggregates induced by substrate rigidity. Soft Matter 8:4578–4583

    Article  Google Scholar 

  164. Wolf K et al (2013) Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J Cell Biol 201:1069–1084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Cóndor M et al (2019) Breast cancer cells adapt contractile forces to overcome steric hindrance. Biophys J 116:1305–1312

    Article  PubMed  PubMed Central  Google Scholar 

  166. Valencia AMJ et al (2015) Collective cancer cell invasion induced by coordinated contractile stresses. Oncotarget 6:43438–43451

    Article  PubMed Central  Google Scholar 

  167. Carey SP, Starchenko A, McGregor AL, Reinhart-King CA (2013) Leading malignant cells initiate collective epithelial cell invasion in a three-dimensional heterotypic tumor spheroid model. Clin Exp Metastasis 30:615–630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Carey SP, Martin KE, Reinhart-King CA (2017) Three-dimensional collagen matrix induces a mechanosensitive invasive epithelial phenotype. Sci Rep 7:42088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Nieto MA, Huang RY-J, Jackson RA, Thiery JP (2016) EMT: 2016. Cell 166:21–45

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  171. Scarpa E et al (2015) Cadherin switch during EMT in neural crest cells leads to contact inhibition of locomotion via repolarization of forces. Dev Cell 34:421–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Hay ED (2005) The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn 233:706–720

    Article  CAS  PubMed  Google Scholar 

  173. Hay ED (1995) An overview of epithelio-mesenchymal transformation. Cells Tissues Organs 154:8–20

    Article  CAS  Google Scholar 

  174. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Friedl P, Mayor R (2017) Tuning collective cell migration by cell–cell junction regulation. Cold Spring Harb Perspect Biol 9:a029199

    Article  PubMed  PubMed Central  Google Scholar 

  176. Campbell K, Casanova J (2016) A common framework for EMT and collective cell migration. Development 143:4291–4300

    Article  CAS  PubMed  Google Scholar 

  177. Barriga EH, Mayor R (2019) Adjustable viscoelasticity allows for efficient collective cell migration. Semin Cell Dev Biol 93:55–68

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  179. Jolly MK et al (2015) Implications of the hybrid epithelial/mesenchymal phenotype in metastasis. Front Oncol 5:155

    Article  PubMed  PubMed Central  Google Scholar 

  180. Aiello NM et al (2018) EMT subtype influences epithelial plasticity and mode of cell migration. Dev Cell 45:681–695.e4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Onder TT et al (2008) Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res 68:3645–3654

    Article  CAS  PubMed  Google Scholar 

  182. Bruner HC, Derksen PWB (2018) Loss of E-cadherin-dependent cell–cell adhesion and the development and progression of cancer. Cold Spring Harb Perspect Biol 10:a029330

    Article  PubMed  PubMed Central  Google Scholar 

  183. Fischer KR et al (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527:472–476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Sutherland A, Keller R, Lesko A (2020) Convergent extension in mammalian morphogenesis. Semin Cell Dev Biol 100:199–211

    Article  CAS  PubMed  Google Scholar 

  187. Tada M, Heisenberg C-P (2012) Convergent extension: using collective cell migration and cell intercalation to shape embryos. Development 139:3897–3904

    Article  CAS  PubMed  Google Scholar 

  188. Wang X et al (2020) Anisotropy links cell shapes to tissue flow during convergent extension. Proc Natl Acad Sci 117:13541–13551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Fredberg JJ (2022) On the origins of order. Soft Matter 18:2346–2353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Atia L, Fredberg JJ, Gov NS, Pegoraro AF (2021) Are cell jamming and unjamming essential in tissue development? Cells Dev 168:203727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. La Porta CAM, Zapperi S (2020) Phase transitions in cell migration. Nat Rev Phys 2:516–517

    Article  Google Scholar 

  192. Weaver VM et al (1997) Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol 137:231–245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Oswald L, Grosser S, Smith DM, Käs JA (2017) Jamming transitions in cancer. J Phys D Appl Phys 50:483001

    Article  PubMed  PubMed Central  Google Scholar 

  194. Brabletz T, Kalluri R, Nieto MA, Weinberg RA (2018) EMT in cancer. Nat Rev Cancer 18:128–134

    Article  CAS  PubMed  Google Scholar 

  195. Käs J et al (2022) Cancer cell motility through unjamming impacts metastatic risk. Preprint at https://doi.org/10.21203/rs.3.rs-1435523/v1

  196. Grosser S et al (2021) Cell and nucleus shape as an indicator of tissue fluidity in carcinoma. Phys Rev X 11:011033

    CAS  Google Scholar 

  197. Guck J et al (2005) Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence. Biophys J 88:3689–3698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Cross SE, Jin Y-S, Rao J, Gimzewski JK (2007) Nanomechanical analysis of cells from cancer patients. Nat Nanotechnol 2:780–783

    Article  CAS  PubMed  Google Scholar 

  199. Fuhs T et al (2021) Rigid tumors contain soft cancer cell. Preprint at https://doi.org/10.21203/rs.3.rs-1114106/v1

  200. Cross SE, Jin Y-S, Rao J, Gimzewski JK (2020) Nanomechanical analysis of cells from cancer patients. In: Nano-enabled medical applications. Jenny Stanford Publishing

    Google Scholar 

  201. Bakir B, Chiarella AM, Pitarresi JR, Rustgi AK (2020) EMT, MET, plasticity, and tumor metastasis. Trends Cell Biol 30:764–776

    Article  PubMed  PubMed Central  Google Scholar 

  202. Hannezo E, Heisenberg C-P (2022) Rigidity transitions in development and disease. Trends Cell Biol 32:433–444

    Article  PubMed  Google Scholar 

  203. Das M, Schmidt CF, Murrell M (2020) Introduction to active matter. Soft Matter 16:7185–7190

    Article  CAS  PubMed  Google Scholar 

  204. Bazellières E et al (2015) Control of cell–cell forces and collective cell dynamics by the intercellular adhesome. Nat Cell Biol 17:409–420

    Article  PubMed  PubMed Central  Google Scholar 

  205. Berthier L, Biroli G (2011) Theoretical perspective on the glass transition and amorphous materials. Rev Mod Phys 83:587–645

    Article  CAS  Google Scholar 

  206. Makse HA, Kurchan J (2002) Testing the thermodynamic approach to granular matter with a numerical model of a decisive experiment. Nature 415:614–617

    Article  CAS  PubMed  Google Scholar 

  207. Loi D, Mossa S, Cugliandolo LF (2008) Effective temperature of active matter. Phys Rev E 77:051111

    Article  Google Scholar 

  208. Manoharan VN (2015) Colloidal matter: packing, geometry, and entropy. Science 349:1253751

    Article  PubMed  Google Scholar 

  209. Zhou EH et al (2009) Universal behavior of the osmotically compressed cell and its analogy to the colloidal glass transition. Proc Natl Acad Sci 106:10632–10637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Angell CA (1985) Spectroscopy simulation and scattering, and the medium range order problem in glass. J Non-Cryst Solids 73:1–17

    Article  CAS  Google Scholar 

  211. Mauro NA, Blodgett M, Johnson ML, Vogt AJ, Kelton KF (2014) A structural signature of liquid fragility. Nat Commun 5:4616

    Article  CAS  PubMed  Google Scholar 

  212. Angell CA, Ueno K (2009) Soft is strong. Nature 462:45–46

    Article  CAS  PubMed  Google Scholar 

  213. Universal glass-forming behavior of in vitro and living cytoplasm | Scientific Reports. https://www.nature.com/articles/s41598-017-14883-y

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

    Article  PubMed  Google Scholar 

  215. Artime O, De Domenico M (2022) From the origin of life to pandemics: emergent phenomena in complex systems. Philos Trans R Soc Math Phys Eng Sci 380:20200410

    Google Scholar 

  216. Geyer D, Martin D, Tailleur J, Bartolo D (2019) Freezing a flock: motility-induced phase separation in polar active liquids. Phys Rev X 9:031043

    CAS  Google Scholar 

  217. Orlanski I (1975) A rational subdivision of scales for atmospheric processes. Bull Am Meteorol Soc 56:527–530

    Google Scholar 

  218. Blanchard GB, Fletcher AG, Schumacher LJ (2019) The devil is in the mesoscale: mechanical and behavioural heterogeneity in collective cell movement. Semin Cell Dev Biol 93:46–54

    Article  PubMed  Google Scholar 

  219. Galeotti G et al (2020) Synthesis of mesoscale ordered two-dimensional π-conjugated polymers with semiconducting properties. Nat Mater 19:874–880

    Article  CAS  PubMed  Google Scholar 

  220. Kleman M, Laverntovich OD (2003) Soft matter physics: an introduction. Springer

    Book  Google Scholar 

  221. Tong H, Tanaka H (2019) Structural order as a genuine control parameter of dynamics in simple glass formers. Nat Commun 10:5596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Thorpe MF (1983) Continuous deformations in random networks. J Non-Cryst Solids 57:355–370

    Article  CAS  Google Scholar 

  223. Lin J, Lerner E, Rosso A, Wyart M (2014) Scaling description of the yielding transition in soft amorphous solids at zero temperature. Proc Natl Acad Sci 111:14382–14387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Leishangthem P, Parmar ADS, Sastry S (2017) The yielding transition in amorphous solids under oscillatory shear deformation. Nat Commun 8:14653

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Nanoscale measurement, Metrology Research Center, National Research Council, Ottawa, ON, Canada

    Adrian F. Pegoraro

  2. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Thien-Khoi N. Phung

  3. Department of Biology, Wesleyan University, Middletown, CT, USA

    Jennifer A. Mitchel

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  2. Thien-Khoi N. Phung
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  3. Jennifer A. Mitchel
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Correspondence to Jennifer A. Mitchel .

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  1. School of Engineering Department of Pathology & Laboratory Medicine Legoretta Cancer Center, Brown University, Providence, RI, USA

    Ian Y. Wong

  2. Department of Molecular Biology, Cell Biology, & Biochemistry, School of Engineering, and Legoretta Cancer Center, Brown University, Providence, RI, USA

    Michelle R. Dawson

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Pegoraro, A.F., Phung, TK.N., Mitchel, J.A. (2023). Collective Cellular Phase Transitions in Cancer. In: Wong, I.Y., Dawson, M.R. (eds) Engineering and Physical Approaches to Cancer. Current Cancer Research. Springer, Cham. https://doi.org/10.1007/978-3-031-22802-5_2

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