TY - JOUR
T1 - Cell adhesion heterogeneity reinforces tumour cell dissemination
T2 - novel insights from a mathematical model
AU - Reher, David
AU - Klink, Barbara
AU - Deutsch, Andreas
AU - Voss-Böhme, Anja
N1 - Funding Information:
DR thanks the Max Planck Digital Library (MPDL) for covering article processing charges. AD and BK are grateful to the Deutsche Krebshilfe for support. AD is supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) within the projects SFB-TR 79 ‘Materials for tissue regeneration within systemically altered bones’ and Research Cluster of Excellence ‘Center for Advancing Electronics Dresden’ (cfaed). AVB is supported by Sächsisches Staatsministerium für Wissenschaft und Kunst (SMWK) in the framework of INTERDIS-2. All authors also thank the Center for Information Services and High Performance Computing (ZIH) at TU Dresden for generous allocation of computational resources.
PY - 2017/8/11
Y1 - 2017/8/11
N2 - BACKGROUND: Cancer cell invasion, dissemination, and metastasis have been linked to an epithelial-mesenchymal transition (EMT) of individual tumour cells. During EMT, adhesion molecules like E-cadherin are downregulated and the decrease of cell-cell adhesion allows tumour cells to dissociate from the primary tumour mass. This complex process depends on intracellular cues that are subject to genetic and epigenetic variability, as well as extrinsic cues from the local environment resulting in a spatial heterogeneity in the adhesive phenotype of individual tumour cells. Here, we use a novel mathematical model to study how adhesion heterogeneity, influenced by intrinsic and extrinsic factors, affects the dissemination of tumour cells from an epithelial cell population. The model is a multiscale cellular automaton that couples intracellular adhesion receptor regulation with cell-cell adhesion.RESULTS: Simulations of our mathematical model indicate profound effects of adhesion heterogeneity on tumour cell dissemination. In particular, we show that a large variation of intracellular adhesion receptor concentrations in a cell population reinforces cell dissemination, regardless of extrinsic cues mediated through the local cell density. However, additional control of adhesion receptor concentration through the local cell density, which can be assumed in healthy cells, weakens the effect. Furthermore, we provide evidence that adhesion heterogeneity can explain the remarkable differences in adhesion receptor concentrations of epithelial and mesenchymal phenotypes observed during EMT and might drive early dissemination of tumour cells.CONCLUSIONS: Our results suggest that adhesion heterogeneity may be a universal trigger to reinforce cell dissemination in epithelial cell populations. This effect can be at least partially compensated by a control of adhesion receptor regulation through neighbouring cells. Accordingly, our findings explain how both an increase in intra-tumour adhesion heterogeneity and the loss of control through the local environment can promote tumour cell dissemination.REVIEWERS: This article was reviewed by Hanspeter Herzel, Thomas Dandekar and Marek Kimmel.
AB - BACKGROUND: Cancer cell invasion, dissemination, and metastasis have been linked to an epithelial-mesenchymal transition (EMT) of individual tumour cells. During EMT, adhesion molecules like E-cadherin are downregulated and the decrease of cell-cell adhesion allows tumour cells to dissociate from the primary tumour mass. This complex process depends on intracellular cues that are subject to genetic and epigenetic variability, as well as extrinsic cues from the local environment resulting in a spatial heterogeneity in the adhesive phenotype of individual tumour cells. Here, we use a novel mathematical model to study how adhesion heterogeneity, influenced by intrinsic and extrinsic factors, affects the dissemination of tumour cells from an epithelial cell population. The model is a multiscale cellular automaton that couples intracellular adhesion receptor regulation with cell-cell adhesion.RESULTS: Simulations of our mathematical model indicate profound effects of adhesion heterogeneity on tumour cell dissemination. In particular, we show that a large variation of intracellular adhesion receptor concentrations in a cell population reinforces cell dissemination, regardless of extrinsic cues mediated through the local cell density. However, additional control of adhesion receptor concentration through the local cell density, which can be assumed in healthy cells, weakens the effect. Furthermore, we provide evidence that adhesion heterogeneity can explain the remarkable differences in adhesion receptor concentrations of epithelial and mesenchymal phenotypes observed during EMT and might drive early dissemination of tumour cells.CONCLUSIONS: Our results suggest that adhesion heterogeneity may be a universal trigger to reinforce cell dissemination in epithelial cell populations. This effect can be at least partially compensated by a control of adhesion receptor regulation through neighbouring cells. Accordingly, our findings explain how both an increase in intra-tumour adhesion heterogeneity and the loss of control through the local environment can promote tumour cell dissemination.REVIEWERS: This article was reviewed by Hanspeter Herzel, Thomas Dandekar and Marek Kimmel.
KW - Cellular automaton
KW - EMT
KW - Intercellular adhesion
KW - Mathematical model
KW - Metastasis
KW - Tumour heterogeneity
KW - Tumour invasion
UR - http://www.scopus.com/inward/record.url?scp=85037150733&partnerID=8YFLogxK
U2 - 10.1186/s13062-017-0188-z
DO - 10.1186/s13062-017-0188-z
M3 - Article
C2 - 28800767
AN - SCOPUS:85037150733
SN - 1745-6150
VL - 12
SP - 18
JO - Biology Direct
JF - Biology Direct
IS - 1
ER -