Spatially heterogeneous dynamics of cells in a growing tumor spheroid: comparison between theory and experiments

Sinha, Sumit; Malmi-Kakkada, Abdul N.; Li, Xin; Samanta, Himadri S.; Thirumalai, D.

doi:10.1039/c9sm02277e

Cited by 48 publications

(34 citation statements)

References 41 publications

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“…defined by sub-diffusive movement with an intermediate time slowdown, as observed in colloidal systems); ( Kegel and van Blaaderen, 2000 ; Weeks et al, 2000 ; Figure 1E,F , blue). The juxtaposition of liquid- and glass-like motion along a single cell-cell junction was interesting, because while fluid-to-glass phase transitions are known features at tissue-level length scales ( Angelini et al, 2011 ; Bi et al, 2015 ; Malmi-Kakkada et al, 2018 ; Sinha et al, 2020 ), such transitions have not been reported at sub-cellular length scales during morphogenesis.…”

Section: Resultsmentioning

confidence: 99%

Mechanical heterogeneity along single cell-cell junctions is driven by lateral clustering of cadherins during vertebrate axis elongation

Huebner

Malmi-Kakkada

Sarıkaya

et al. 2021

eLife

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Morphogenesis is governed by the interplay of molecular signals and mechanical forces across multiple length scales. The last decade has seen tremendous advances in our understanding of the dynamics of protein localization and turnover at sub-cellular length scales, and at the other end of the spectrum, of mechanics at tissue-level length scales. Integrating the two remains a challenge, however, because we lack a detailed understanding of the subcellular patterns of mechanical properties of cells within tissues. Here, in the context of the elongating body axis of Xenopus embryos, we combine tools from cell biology and physics to demonstrate that individual cell-cell junctions display finely-patterned local mechanical heterogeneity along their length. We show that such local mechanical patterning is essential for the cell movements of convergent extension and is imparted by locally patterned clustering of a classical cadherin. Finally, the patterning of cadherins and thus local mechanics along cell-cell junctions are controlled by Planar Cell Polarity signaling, a key genetic module for CE that is mutated in diverse human birth defects.

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Section: Resultsmentioning

confidence: 99%

Mechanical heterogeneity along single cell-cell junctions is driven by lateral clustering of cadherins during vertebrate axis elongation

Huebner

Malmi-Kakkada

Sarıkaya

et al. 2021

eLife

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“…1E, F, blue ). The juxtaposition of liquid- and glass-like motion along a single cell-cell junction was interesting, because while fluid-to-glass phase transitions are known features at tissue-level length scales (Angelini et al, 2011; Bi et al, 2015; Malmi-Kakkada et al, 2018; Sinha et al, 2020), such transitions have not been reported at sub-cellular length scales during morphogenesis. To confirm this surprising result, we applied four additional physical metrics, the Van Hove function, the velocity auto-correlation function, the self-overlap parameter, and the fourth order susceptibility, χ 4 ( t ) ( SI sections 2-4 ).…”

Section: Resultsmentioning

confidence: 99%

Mechanical heterogeneity along single cell-cell junctions is driven by lateral clustering of cadherins during vertebrate axis elongation

Huebner

Malmi-Kakkada

Sarıkaya

et al. 2020

Preprint

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Tissue morphogenesis requires the control of physical forces by molecular patterning systems encoded in the genome. For example, tissue-level mechanical transformations in vertebrate embryos require the activity of cadherin adhesion proteins and the Planar Cell Polarity (PCP) signaling system. At the tissue level, collective cell movements are known to be highly complex, displaying combinations of fluid/solid behaviors, jamming transitions, and glass-like dynamics. The sub-cellular origin of these heterogeneous tissue dynamics is undefined. Here, high-speed super-resolution imaging and physical methods for quantifying motion revealed that the subcellular behaviors underlying vertebrate embryonic axis elongation display glass-like dynamic heterogeneities. A combination of theory and experiment demonstrates these behaviors are highly local, displaying asymmetries even within individual cell-cell junctions. Moreover, we demonstrate that these mechanical asymmetries require patterned lateral (cis-) clustering of cadherins that is dependent upon PCP signaling. These findings illuminate the mechanisms by which defined molecular patterning systems tune the mechanics of sub-cellular behaviors that drive vertebrate axis elongation. Introduction:

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“…Additional complexities on fusion dynamics could arise as cells enter a pressuredependent dormant state, increasing tissue heterogeneity. For example, the increased pressure in the core of tumor spheroids results in a jammed stage with dormant cells, while cells at the periphery grow and motility is super-diffusive [36].…”

Section: Discussionmentioning

confidence: 99%

Activity-Induced Fluidization and Arrested Coalescence in Fusion of Cellular Aggregates

et al. 2021

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At long time scales, tissue spheroids may flow or appear solid depending on their capacity to reorganize their internal structure. Understanding the relationship between intrinsic mechanical properties at the single cell level, and the tissue spheroids dynamics at the long-time scale is key for artificial tissue constructs, which are assembled from multiple tissue spheroids that over time fuse to form coherent structures. The dynamics of this fusion process are frequently analyzed in the framework of liquid theory, wherein the time scale of coalescence of two droplets is governed by its radius, viscosity and surface tension. In this work, we extend this framework to glassy or jammed cell behavior which can be observed in spheroid fusion. Using simulations of an individual-cell based model, we demonstrate how the spheroid fusion process can be steered from liquid to arrested by varying active cell motility and repulsive energy as established by cortical tension. The divergence of visco-elastic relaxation times indicates glassy relaxation near the transition toward arrested coalescence. Finally, we investigate the role of cell growth in spheroid fusion dynamics. We show that the presence of cell division introduces plasticity in the material and thereby increases coalescence during fusion.

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Spatially heterogeneous dynamics of cells in a growing tumor spheroid: comparison between theory and experiments

Abstract: Spatially heterogenous dynamics inside a growing tumor spheroid.

Cited by 48 publications

References 41 publications

Mechanical heterogeneity along single cell-cell junctions is driven by lateral clustering of cadherins during vertebrate axis elongation

Mechanical heterogeneity along single cell-cell junctions is driven by lateral clustering of cadherins during vertebrate axis elongation

Mechanical heterogeneity along single cell-cell junctions is driven by lateral clustering of cadherins during vertebrate axis elongation

Activity-Induced Fluidization and Arrested Coalescence in Fusion of Cellular Aggregates

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