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Emergent Stratification in Solid Tumors Selects for Reduced Cohesion of Tumor Cells: A Multi-Cell, Virtual-Tissue Model of Tumor Evolution Using CompuCell3D.

Swat MH, Thomas GL, Shirinifard A, Clendenon SG, Glazier JA - PLoS ONE (2015)

Bottom Line: Our model includes essential cell behaviors, microenvironmental components and their interactions.Our model provides a platform for exploring selection pressures leading to the evolution of tumor-cell aggression, showing that emergent stratification into regions with different cell survival rates drives the evolution of less cohesive cells with lower levels of cadherins and higher levels of integrins.Such reduced cohesivity is a key hallmark in the progression of many types of solid tumors.

View Article: PubMed Central - PubMed

Affiliation: Biocomplexity Institute and Department of Physics, Indiana University, Bloomington, Indiana, USA.

ABSTRACT
Tumor cells and structure both evolve due to heritable variation of cell behaviors and selection over periods of weeks to years (somatic evolution). Micro-environmental factors exert selection pressures on tumor-cell behaviors, which influence both the rate and direction of evolution of specific behaviors, especially the development of tumor-cell aggression and resistance to chemotherapies. In this paper, we present, step-by-step, the development of a multi-cell, virtual-tissue model of tumor somatic evolution, simulated using the open-source CompuCell3D modeling environment. Our model includes essential cell behaviors, microenvironmental components and their interactions. Our model provides a platform for exploring selection pressures leading to the evolution of tumor-cell aggression, showing that emergent stratification into regions with different cell survival rates drives the evolution of less cohesive cells with lower levels of cadherins and higher levels of integrins. Such reduced cohesivity is a key hallmark in the progression of many types of solid tumors.

No MeSH data available.


Related in: MedlinePlus

Evolution of typical generalized-cell cohesivity vs. time.A) Average density of cadherin (Cad) of tumor generalized cells in arbitrary units (AU) vs. time. B) Average density of integrin (Int) of tumor generalized cells in arbitrary units (AU) vs. time. C) Average surface tension between tumor generalized cells and Medium vs. time.
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pone.0127972.g004: Evolution of typical generalized-cell cohesivity vs. time.A) Average density of cadherin (Cad) of tumor generalized cells in arbitrary units (AU) vs. time. B) Average density of integrin (Int) of tumor generalized cells in arbitrary units (AU) vs. time. C) Average surface tension between tumor generalized cells and Medium vs. time.

Mentions: In our model, invasion of Medium is a winning strategy for generalized cells. Generalized cells gain invasive behaviors in two key phases. In the initial phase, as long as generalized cells remain in clusters, differential cell adhesion leads to cell-sorting in which generalized cells expressing lower levels of cadherins and higher levels of integrins (relative to the typical levels in the cluster) move to the surface of the cluster and generalized cells expressing higher levels of cadherins (relative to typical values in the cluster) move towards the center of the cluster (the black arrow in Fig 4C). As generalized cells move towards the center of the cluster, they cease to proliferate, starve and eventually die. Thus generalized cells which remain on the surface of the cluster proliferate more rapidly than those in the interior of the cluster, selecting for the least cohesive generalized cells in the cluster. Since a generalized cell’s cadherin level has a greater effect on its radial position in the cluster than its integrin level, initial selection predominantly favors generalized cells with decreased cadherin levels (Fig 4A). Because starvation selects for lower relative adhesion between generalized cells, the typical cadherin level of the generalized cells in the cluster decreases continuously until, in the second phase, the least cohesive generalized cells (those with high levels of integrin and low levels of cadherin) in the cluster are able to migrate out of the cluster. This invasive phenotype corresponds to a negative surface tension between Medium and tumor generalized cells (Fig 2C.2, Fig 4B–4C). As we discussed in section “Size and Shape Dynamics”, invasive generalized cells then come to dominate the tumor-cell population, and spread throughout the Medium.


Emergent Stratification in Solid Tumors Selects for Reduced Cohesion of Tumor Cells: A Multi-Cell, Virtual-Tissue Model of Tumor Evolution Using CompuCell3D.

Swat MH, Thomas GL, Shirinifard A, Clendenon SG, Glazier JA - PLoS ONE (2015)

Evolution of typical generalized-cell cohesivity vs. time.A) Average density of cadherin (Cad) of tumor generalized cells in arbitrary units (AU) vs. time. B) Average density of integrin (Int) of tumor generalized cells in arbitrary units (AU) vs. time. C) Average surface tension between tumor generalized cells and Medium vs. time.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4470639&req=5

pone.0127972.g004: Evolution of typical generalized-cell cohesivity vs. time.A) Average density of cadherin (Cad) of tumor generalized cells in arbitrary units (AU) vs. time. B) Average density of integrin (Int) of tumor generalized cells in arbitrary units (AU) vs. time. C) Average surface tension between tumor generalized cells and Medium vs. time.
Mentions: In our model, invasion of Medium is a winning strategy for generalized cells. Generalized cells gain invasive behaviors in two key phases. In the initial phase, as long as generalized cells remain in clusters, differential cell adhesion leads to cell-sorting in which generalized cells expressing lower levels of cadherins and higher levels of integrins (relative to the typical levels in the cluster) move to the surface of the cluster and generalized cells expressing higher levels of cadherins (relative to typical values in the cluster) move towards the center of the cluster (the black arrow in Fig 4C). As generalized cells move towards the center of the cluster, they cease to proliferate, starve and eventually die. Thus generalized cells which remain on the surface of the cluster proliferate more rapidly than those in the interior of the cluster, selecting for the least cohesive generalized cells in the cluster. Since a generalized cell’s cadherin level has a greater effect on its radial position in the cluster than its integrin level, initial selection predominantly favors generalized cells with decreased cadherin levels (Fig 4A). Because starvation selects for lower relative adhesion between generalized cells, the typical cadherin level of the generalized cells in the cluster decreases continuously until, in the second phase, the least cohesive generalized cells (those with high levels of integrin and low levels of cadherin) in the cluster are able to migrate out of the cluster. This invasive phenotype corresponds to a negative surface tension between Medium and tumor generalized cells (Fig 2C.2, Fig 4B–4C). As we discussed in section “Size and Shape Dynamics”, invasive generalized cells then come to dominate the tumor-cell population, and spread throughout the Medium.

Bottom Line: Our model includes essential cell behaviors, microenvironmental components and their interactions.Our model provides a platform for exploring selection pressures leading to the evolution of tumor-cell aggression, showing that emergent stratification into regions with different cell survival rates drives the evolution of less cohesive cells with lower levels of cadherins and higher levels of integrins.Such reduced cohesivity is a key hallmark in the progression of many types of solid tumors.

View Article: PubMed Central - PubMed

Affiliation: Biocomplexity Institute and Department of Physics, Indiana University, Bloomington, Indiana, USA.

ABSTRACT
Tumor cells and structure both evolve due to heritable variation of cell behaviors and selection over periods of weeks to years (somatic evolution). Micro-environmental factors exert selection pressures on tumor-cell behaviors, which influence both the rate and direction of evolution of specific behaviors, especially the development of tumor-cell aggression and resistance to chemotherapies. In this paper, we present, step-by-step, the development of a multi-cell, virtual-tissue model of tumor somatic evolution, simulated using the open-source CompuCell3D modeling environment. Our model includes essential cell behaviors, microenvironmental components and their interactions. Our model provides a platform for exploring selection pressures leading to the evolution of tumor-cell aggression, showing that emergent stratification into regions with different cell survival rates drives the evolution of less cohesive cells with lower levels of cadherins and higher levels of integrins. Such reduced cohesivity is a key hallmark in the progression of many types of solid tumors.

No MeSH data available.


Related in: MedlinePlus