8th Annual Symposium
Physics of Cancer
October 4-6, 2017
|PoC - Physics of Cancer - Annual Symposium|
Unjamming and cell shape changes in breast cancer
Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, Massachusetts, USA
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Cancer cells most often invade neighboring tissues as collective groups, e.g. protruding sheets, clusters or strands [Friedl et al. Nat cell bio 14, 777, 2012]. Dogma holds that in order to migrate such cells would have to undergo an epithelial-to-mesenchymal transition (EMT) or partial EMT [Lambert et al. Cell 168, 670, 2017]. But to the contrary, these migrating clusters retain epithelial markers [Cheung et al., Cell 155, 1639, 2013; Fischer et al., Nature 527, 472, 2015; Zheng, X. F. et al., Nature 527, 525, 2015]. This finding suggests that instead of EMT, some alternative migratory program might be activated. Here we propose that such a program might be provided by the unjamming transition, a process in which a cellular collective undergoes a transition from a solid-like phase to a liquid-like phase [Park & Kim et al. Nat Mater 14, 1040, 2015]. This transition is marked not by EMT markers but by characteristic changes of cell shape [Bi et al. Nat Phys 11, 1074 2015]. Across vastly diverse epithelial systems, cell shape variation collapses to a family of distributions that is common to all and potentially universal; as a cell layer becomes more and more unjammed, cell shape becomes progressively elongated and more variable [Atia et al., arXiv].
Using genetically engineered breast-cancer models, MCF10A cells expressing vector, ErbB2 and 14-3-3ζ [Lu et al. Cancer cell 16, 195, 2009], we tested how diverse levels of transforming potential affect the jamming index, cell shape. Surprisingly, regardless of transforming potential, expression of cell–cell adhesion, or cell proliferation, cell shape variation of all three MCF10A cell lines fall on the same distribution. Moreover, compared to control vector cells, ErbB2 cells that are highly proliferative or 14-3-3ζ cells that lack E-cadherin tended to be elongated and more variable in their shapes showing that tumorigenic cells tend to be more unjammed. We then tested the theoretical prediction in which as adhesion outcompete cortical contraction cells tend to be elongated and to be more unjammed [Bi et al. Nat Phys 11, 1074 2015; Atia et al., arXiv]. Indeed, when we measured adhesion forces exerted across cell-cell adhesion in three cell lines, adhesion forces were larger in ErbB2 and 14-3-3ζ cells that are more unjammed versus control cells. When we tested this prediction in a highly malignant breast cancer cell line, MDA-MB-231, versus non-malignant cell line, MCF10A, adhesion forces were not statistically different, but tended to be larger in MDA-MB-231 cells. Note that in both of MCF10A.14-3-3ζ and MDA-MB-231cells loss of E-cadherin did not abolish adhesion forces; this observation contradicts the prevailing dogma in which loss of cell-cell adhesion is required for tumor cell migration, but instead suggests that increased adhesion forces promote unjamming.
Together, these results suggest that unjamming provides tumor cells a gateway to collective cellular motility.