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  • Open Access

Nuclear Packing Sets Fluidity Along the Epithelial to Mesenchymal Spectrum

Karen Yu1,2, Alexander J. Devanny1, and Laura J. Kaufman1,*

  • *Contact author: kaufman@chem.columbia.edu
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PRX Life 4, 033011 – Published 5 August, 2026

DOI: https://doi.org/10.1103/1thq-kysn

Abstract

Investigations of jamming in cancer have produced numerous phase diagrams intending to map fluidity across the epithelial-to-mesenchymal transition (EMT). Here, we use coalescence of multicellular spheroids to examine and carefully probe these phase spaces. Small changes in cellular EMT status result in full traversal of the solid-to-fluid continuum. Variations in fluidity as measured by degree of spheroid coalescence are captured by two-dimensional assessment of static cellular properties including internuclear spacing and nuclear shape, which can be determined in individual noninteracting spheroids. We combine these quantities into an effective nuclear packing metric that depends on nuclear occupancy and nuclear elongation. We find that dense nuclear packing impedes spheroid coalescence and that lowering effective nuclear packing by altering nuclear shape fluidizes an otherwise solidlike system. Furthermore, we employ heterotypic spheroids to tune effective nuclear packing and coalescence behavior, thus introducing a novel method of fluidity phase space exploration. Together, these findings reveal that nuclear occupancy and morphology act as important indicators and determinants of fluidity.

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References (72)

  1. L. Oswald, S. Grosser, D. M. Smith, and J. A. Käs, Jamming transitions in cancer, J. Phys. Appl. Phys. 50, 483001 (2017).
  2. J.-A. Park and J. J. Fredberg, Cell jamming in the airway epithelium, Ann. Am. Thorac. Soc. 13, S64 (2016).
  3. X. Wang, M. Merkel, L. B. Sutter, G. Erdemci-Tandogan, M. L. Manning, and K. E. Kasza, Anisotropy links cell shapes to tissue flow during convergent extension, Proc. Natl. Acad. Sci. USA 117, 13541 (2020).
  4. A. Mongera, P. Rowghanian, H. J. Gustafson, E. Shelton, D. A. Kealhofer, E. K. Carn, F. Serwane, A. A. Lucio, J. Giammona, and O. Campàs, A fluid-to-solid jamming transition underlies vertebrate body axis elongation, Nature (London) 561, 401 (2018).
  5. A. J. Liu and S. R. Nagel, Jamming is not just cool any more, Nature (London) 396, 21 (1998).
  6. V. Trappe, V. Prasad, L. Cipelletti, P. N. Segre, and D. A. Weitz, Jamming phase diagram for attractive particles, Nature (London) 411, 772 (2001).
  7. T. E. Angelini, E. Hannezo, X. Trepat, M. Marquez, J. J. Fredberg, and D. A. Weitz, Glass-like dynamics of collective cell migration, Proc. Natl. Acad. Sci. USA 108, 4714 (2011).
  8. E. Lawson-Keister and M. L. Manning, Jamming and arrest of cell motion in biological tissues, Curr. Opin. Cell Biol. 72, 146 (2021).
  9. A. J. Liu and S. R. Nagel, The jamming transition and the marginally jammed solid, Annu. Rev. Condens. Matter Phys. 1, 347 (2010).
  10. P. Gottheil, J. Lippoldt, S. Grosser, F. Renner, M. Saibah, D. Tschodu, A-K. Poßögel, A-S. Wegscheider, B. Ulm, K. Friedrichs, et al., State of cell unjamming correlates with distant metastasis in cancer patients, Phys. Rev. X 13, 031003 (2023).
  11. S. Grosser, J. Lippoldt, L. Oswald, M. Merkel, D. M. Sussman, F. Renner, P. Gottheil, E. W. Morawetz, T. Fuhs, X. Xie, et al., Cell and nucleus shape as an indicator of tissue fluidity in carcinoma, Phys. Rev. X 11, 011033 (2021).
  12. W. Kang, J. Ferruzzi, C-P. Spatarelu, Y. L. Han, Y. Sharma, S. A. Koehler, J. A. Mitchel, A. Khan, J. P. Butler, D. Roblyer, et al., A novel jamming phase diagram links tumor invasion to non-equilibrium phase separation, iScience 24, 103252 (2021).
  13. O. Ilina, P. G. Gritzenko, S. Syga, J. Lippoldt, G. A. M. La Porta, O. Chepizhko, S. Grosser, M. Vullings, G. -J. Bakker, J. Starruß, et al., Cell–cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion, Nat. Cell Biol. 22, 1103 (2020).
  14. D. Bi, X. Yang, M. C. Marchetti, and M. L. Manning, Motility-driven glass and jamming transitions in biological tissues, Phys. Rev. X 6, 021011 (2016).
  15. M. Chiang and D. Marenduzzo, Glass transitions in the cellular Potts model, Europhys. Lett. 116, 28009 (2016).
  16. J. Huang, H. Levine, and D. Bi, Bridging the gap between collective motility and epithelial–mesenchymal transitions through the active finite Voronoi model, Soft Matter 19, 9389 (2023).
  17. D. Bi, J. H. Lopez, J. M. Schwarz, and M. L. Manning, A density-independent rigidity transition in biological tissues, Nat. Phys. 11, 1074 (2015).
  18. J. Abel, S. Jain, D. Rajan, H. Padigela, K. Leidal, A. Prakash, J. Conway, M. Nercessian, C. Kirkup, S. A. Javed, et al., AI powered quantification of nuclear morphology in cancers enables prediction of genome instability and prognosis, Npj Precis. Oncol. 8, 134 (2024).
  19. N. F. de Leeuw, R. Budhathoki, L. J. Russell, D. Loerke, and J. T. Blankenship, Nuclei as mechanical bumpers during epithelial remodeling, J. Cell Biol. 223, e202405078 (2024).
  20. W. Tang, J. Huang, A. F. Pegoraro, J. H. Zhang, Y. Tang, D. N. Kotton, D. Bi, and M. Guo, Topology and nuclear size determine cell packing on growing lung spheroids, Phys. Rev. X 15, 011067 (2025).
  21. P. M. Davidson, C. Denais, M. C. Bakshi, and J. Lammerding, Nuclear deformability constitutes a rate-limiting step during cell migration in 3-D environments, Cell. Mol. Bioeng. 7, 293 (2014).
  22. K. Wolf, M. te Lindert, M. Krause, S. Alexander, J. te Riet, A. L. Willis, R. M. Hoffman, C. G. Figdor, S. J. Weiss, and P. Friedl, Physical limits of cell migration: Control by ECM space and nuclear deformation and tuning by proteolysis and traction force, J. Cell Biol. 201, 1069 (2013).
  23. S. Kim, R. Amini, S.-T. Yen, P. Pospíšil, A. Boutillon, I. A. Deniz, and O. Campàs, A nuclear jamming transition in vertebrate organogenesis, Nat. Mater. 23, 1592 (2024).
  24. E. Antmen, U. Demirci, and V. Hasirci, Amplification of nuclear deformation of breast cancer cells by seeding on micropatterned surfaces to better distinguish their malignancies, Colloids Surf. B: Biointerfaces 183, 110402 (2019).
  25. A. Guzman, M. J. Ziperstein, and L. J. Kaufman, The effect of fibrillar matrix architecture on tumor cell invasion of physically challenging environments, Biomaterials 35, 6954 (2014).
  26. T. Fuhs, F. Wetzel, A. W. Fritsch, X. Li, R. Stange, S. Pawlizak, T. R. Kießling, E. Morawetz, S. Grosser, F. Sauer, J. Lippoldt, et al., Rigid tumours contain soft cancer cells, Nat. Phys. 18, 1510 (2022).
  27. N. V. Kosheleva, Y. M. Efremov, B. S. Shavkuta, I. M. Zurina, D. Zhang, Y. Zhang, N. V. Minaev, A. A. Gorkun, S. Wei, A. I. Shpichka, et al., Cell spheroid fusion: Beyond liquid drops model, Sci. Rep. 10, 12614 (2020).
  28. G. C. J. Lindberg, X. Cui, M. Durham, L. Veenendaal, B. S. Schon, G. J. Hooper, K. S. Lim, and T. B. F. Woodfield, Probing multicellular tissue fusion of cocultured spheroids—A 3D-bioassembly model, Adv. Sci. 8, e2103320 (2021).
  29. S. Ongenae, M. Cuvelier, J. Vangheel, H. Ramon, and B. Smeets, Activity-induced fluidization and arrested coalescence in fusion of cellular aggregates, Front. Phys. 9, 649821 (2021).
  30. D. Oriola, M. Marin-Riera, K. Anlaş, N. Gritti, M. Sanaki-Matsumiya, G. Aalderink, M. Ebisuya, J. Sharpe, and V. Trivedi, Arrested coalescence of multicellular aggregates, Soft Matter 18, 3771 (2022).
  31. G. L. Thomas, V. Mironov, A. Nagy-Mehez, and J. C. M. Mombach, Dynamics of cell aggregates fusion: Experiments and simulations, Phys. Stat. Mech. Appl. 395, 247 (2014).
  32. J. Lammerding, Mechanics of the nucleus, Compr. Physiol. 1, 783 (2011).
  33. N. Barnabas and D. Cohen, Phenotypic and molecular characterization of MCF10DCIS and SUM breast cancer cell lines, Int. J. Breast Cancer 2013, 872743 (2013).
  34. J. Samson, M. Derlipanska, O. Zaheed, and K. Dean, Molecular and cellular characterization of two patient-derived ductal carcinoma in situ (DCIS) cell lines, ETCC-006 and ETCC-010, BMC Cancer 21, 790 (2021).
  35. Q. Li and R. R. Mattingly, Restoration of E-cadherin cell-cell junctions requires both expression of E-cadherin and suppression of ERK MAP kinase activation in Ras-transformed breast epithelial cells, Neoplasia 10, 1444 (2008).
  36. J. Y. So, H. J. Lee, P. Kramata, A. Minden, and N. Suh, Differential expression of key signaling proteins in MCF10 cell lines, a human breast cancer progression model, Mol. Cell. Pharmacol. 4, 31 (2012).
  37. Z. Hajdu, V. Mironov, A. N. Mehesz, R. A. Norris, R. R. Markwald, and R. P. Visconti, Tissue spheroid fusion-based in vitro screening assays for analysis of tissue maturation, J. Tissue Eng. Regen. Med. 4, 659 (2010).
  38. M. J. Susienka, B. T. Wilks, and J. R. Morgan, Quantifying the kinetics and morphological changes of the fusion of spheroid building blocks, Biofabrication 8, 045003 (2016).
  39. T. Y. Kim, C. M. Kofron, M. E. King, A. R. Markes, A. O. Okundaye, Z. Qu, U. Mende, and B.-R. Choi, Directed fusion of cardiac spheroids into larger heterocellular microtissues enables investigation of cardiac action potential propagation via cardiac fibroblasts, PLoS ONE 13, e0196714 (2018).
  40. Y. Kuroda and J. Furuyama, Physiological and biochemical studies of effects of mitomycin C on strain HeLa cells in cell culture, Cancer Res. 23, 682 (1963).
  41. E. Leal-Orta, J. Ramirez-Ricardo, P. Cortes-Reynosa, O. Galindo-Hernandez, and E. P. Salazar, Role of PI3K/Akt on migration and invasion of MCF10A cells treated with extracellular vesicles from MDA-MB-231 cells stimulated with linoleic acid, J. Cell Commun. Signal. 13, 235 (2019).
  42. J. Ranft, M. Basan, J. Elgeti, J.-F. Joanny, J. Prost, and F. Jülicher, Fluidization of tissues by cell division and apoptosis, Proc. Natl. Acad. Sci. USA 107, 20863 (2010).
  43. H. Yue, J. C. Burton, and D. M. Sussman, Coalescing clusters unveil regimes of frictional fluid mechanics, Phys. Rev. Res. 6, 023115 (2024).
  44. A. B. Pawar, M. Caggioni, R. W. Hartel, and P. T. Spicer, Arrested coalescence of viscoelastic droplets with internal microstructure, Farad. Discuss. 158, 341 (2012).
  45. G. Dechristé, J. Fehrenbach, E. Griseti, V. Lobjois, and C. Poignard, Viscoelastic modeling of the fusion of multicellular tumor spheroids in growth phase, J. Theor. Biol. 454, 102 (2018).
  46. T. A. Sharp, M. Merkel, M. L. Manning, and A. J. Liu, Inferring statistical properties of 3D cell geometry from 2D slices, PLoS ONE 14, e0209892 (2019).
  47. F. Y. Zhou, Z. Marin, C. Yapp, Q. Zou, B. A. Nanes, S. Daetwyler, A. R. Jamieson, M. T. Islam, E. Jenkins, G. M. Gihana, et al., Universal consensus 3D segmentation of cells from 2D segmented stacks, Nat. Methods 22, 2386 (2025).
  48. L. Atia, D. Bi, Y. Sharma, J. A. Mitchel, B. Gweon, S. A. Koehler, S. J. DeCamp, B. Lan, J. H. Kim, R. Hirsch, et al., Geometric constraints during epithelial jamming, Nat. Phys. 14, 613 (2018).
  49. J. H. Kim, A. F. Pegoraro, A. Das, S. A. Koehler, S. A. Ujwary, B. Lan, J. A. Mitchel, L. Atia, S. He, K. Wang, et al., Unjamming and collective migration in MCF10A breast cancer cell lines, Biochem. Biophys. Res. Commun. 521, 706 (2020).
  50. P. Arora, S. Sadhukhan, S. K. Nandi, D. Bi, A. K. Sood, and R. Ganapathy, A shape-driven reentrant jamming transition in confluent monolayers of synthetic cell-mimics, Nat. Commun. 15, 5645 (2024).
  51. L. A. Lautscham, C. Kämmerer, J. R. Lange, T. Kolb, C. Mark, A. Schilling, P. L. Strissel, R. Strick, C. Gluth, A. C. Rowat, et al., Migration in confined 3D environments is determined by a combination of adhesiveness, nuclear volume, contractility, and cell stiffness, Biophys. J. 109, 900 (2015).
  52. A. L. McGregor, C.-R. Hsia, and J. Lammerding, Squish and squeeze—The nucleus as a physical barrier during migration in confined environments, Curr. Opin. Cell Biol. 40, 32 (2016).
  53. S.-J. Heo, K. H. Song, S. Thakur, L. M. Miller, X. Cao, A. P. Peredo, B. N. Seiber, F. Qu, T. P. Driscoll, V. B. Shenoy, et al., Nuclear softening expedites interstitial cell migration in fibrous networks and dense connective tissues, Sci. Adv. 6, eaax5083 (2020).
  54. T. Fischer, A. Hayn, and C. T. Mierke, Effect of nuclear stiffness on cell mechanics and migration of human breast cancer cells, Front. Cell Dev. Biol. 8, 393 (2020).
  55. R. C. Locke, L. M. Miller, E. A. Lemmon, S. S. Assi, D. L. Jones, E. D. Bonnevie, J. A. Burdick, S. J. Heo, and R. L. Mauck, Rapid restoration of cell phenotype and matrix forming capacity following transient nuclear softening, Acta Biomater. 208, 336 (2025).
  56. A. Mitra, M. F. A. Cutiongco, R. Burla, Y. Zeng, Q. Na, M. Kong, B. Vinod, M. H. Nai, B. Hübner, A. Ludwig, et al., Acute chromatin decompaction stiffens the nucleus as revealed by nanopillar-induced nuclear deformation in cells, Proc. Natl. Acad. Sci. USA 122, e2416659122 (2025).
  57. R. J. Tetley, M. F. Staddon, D. Heller, A. Hoppe, S. Banerjee, and Y. Mao, Tissue fluidity promotes epithelial wound healing, Nat. Phys. 15, 1195 (2019).
  58. S. Ongenae, H. Svitina, T. E. R. Belpaire, J. Vangheel, T. Martens, P. Vanden Berghe, I. Papantoniou, and B. Smeets, Active foam dynamics of tissue spheroid fusion, Nat. Commun. 16, 10467 (2025).
  59. A. J. Devanny, M. B. Vancura, and L. J. Kaufman, Exploiting differential effects of actomyosin contractility to control cell sorting among breast cancer cells, Mol. Biol. Cell 32, 24 (2021).
  60. Y. L. Han, A. F. Pegoraro, H. Li, K. Li, Y. Yuan, G. Xu, Z. Gu, J. Sun, Y. Hao, S. K. Gupta, et al., Cell swelling, softening and invasion in a three-dimensional breast cancer model, Nat. Phys. 16, 101 (2020).
  61. F. Lüönd, S. Tiede, and G. Christofori, Breast cancer as an example of tumour heterogeneity and tumour cell plasticity during malignant progression, Br. J. Cancer 125, 164 (2021).
  62. M. Gamboa Castro, S. E. Leggett, and I. Y. Wong, Clustering and jamming in epithelial–mesenchymal co-cultures, Soft Matter 12, 8327 (2016).
  63. X. Li, A. Das, and D. Bi, Mechanical heterogeneity in tissues promotes rigidity and controls cellular invasion, Phys. Rev. Lett. 123, 058101 (2019).
  64. K. J. Pienta and D. S. Coffey, Correlation of nuclear morphometry with progression of breast cancer, Cancer 68, 2012 (1991).
  65. W. H. Wolberg, W. N. Street, and O. L. Mangasarian, Importance of nuclear morphology in breast cancer prognosis, Clin. Cancer Res. 5, 3542 (1999).
  66. M.-K. Hayward, J. L. Jones, A. Hall, L. King, A. J. Ironside, A. C. Nelson, E. S. Hwang, and V. M. Weaver, Derivation of a nuclear heterogeneity image index to grade DCIS, Comput. Struct. Biotechnol. J. 18, 4063 (2020).
  67. J. Chang, A. Saraswathibhatla, Z. Song, S. Varma, C. Sanchez, N. H. K. Alyafei, D. Indana, R. Slyman, S. Srivastava, K. Liu, et al., Cell volume expansion and local contractility drive collective invasion of the basement membrane in breast cancer, Nat. Mater. 23, 711 (2024).
  68. H. Lee, R. Stowers, and O. Chaudhuri, Volume expansion and TRPV4 activation regulate stem cell fate in three-dimensional microenvironments, Nat. Commun. 10, 529 (2019).
  69. K. Miura, Bleach correction ImageJ plugin for compensating the photobleaching of time-lapse sequences, F1000Research 9, 1494 (2020).
  70. M. Pachitariu, M. Rariden, and C. Stringer, Cellpose-SAM: Superhuman generalization for cellular segmentation, bioRxiv (2025), https://doi.org/10.1101/2025.04.28.651001.
  71. S. Van Der Walt, J. L. Schönberger, J. Nunez-Iglesias, F. Boulogne, J. D. Warner, N. Yager, E. Gouillart, and T. Yu, Scikit-image: Image processing in python, PeerJ 2, e453 (2014).
  72. U. Schmidt, M. Weigert, C. Broaddus, and G. Myers, Cell detection with star-convex polygons, in Medical Image Computing and Computer Assisted Intervention–MICCAI 2018, edited by A. F. Frangi, J. A. Schnabel, C. Davatzikos, C. Alberola-López, and G. Fichtinger (Springer International Publishing, Cham, 2018), Vol. 11071, pp. 265–273.

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PRX Life 4, 033011– Published 5 August, 2026
  • Received 25 October 2025
  • Accepted 11 June 2026
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