How cells initiate Epithelial-to-Mesenchymal Transition? A computational modelling of cellular and supra-cellular networks to unravel the control of EMT.
Creators: name: Pais, Ricardo Jorge
Publisher: name: figshare
Year: 2019
Subjects: subject: Computational Biology
subject: 60102 Bioinformatics
subject: FOS: Computer and information sciences
subject: FOS: Computer and information sciences

description: The objective of this thesis is to provide an integrative (holistic) computational approach to better understand how Epithelial-to-Mesenchymal transition (EMT) is controlled by the microenvironment in the context of cancer and metastasis. Since EMT regulation is complex, we focus on cell-cell adhesion and focal adhesion dynamics as proxies for the main phenotypes involved in the process of metastasis (Epithelial, Mesenchymal and Hybrid phenotypes). Therefore, we developed a literature-based logical network model, accounting for 8 key microenvironment signals as model inputs, 9 key signalling pathways or regulatory mechanisms, and two cell adhesion properties as model readouts that describe phenotypes. The model was able to recapitulate the observed activity degrees of 9 Epithelial/Mesenchymal markers, reported activity patterns of pathways, and 169 observations from 13 experiments on Epithelial cell lines. Next, we aimed to interrogate the model to generate novel predictions for the control of the switching between phenotypes. Strikingly, the model-based analysis showed that RPTP activation by cell-cell contacts (model input) prevented the switching from Epithelial to Mesenchymal/Hybrid phenotype in the presence of signals that promote EMT. The model-based analysis also showed that RPTP activation triggered the switching from Mesenchymal/Hybrid to Epithelial phenotype. These results suggest that RPTP could play a role as a control mechanism of EMT. In addition, the model-based analysis showed that the combination of ROS with an EMT promoting signal inhibited the RPTP control mechanism. This explained the observed correlation between metastasis and the combination of hypoxia with chronic inflammation signals. Perturbation analysis on model components (e.g KO or Ectopic activation) resulted in the identification of 23 single and 24 double perturbations that either stabilized the Hybrid phenotype or destabilized the Epithelial/Mesenchymal phenotypes, suggesting possible critical intra-cellular alterations. Among these, SRC ectopic activation destabilized the Epithelial phenotype and FAT4 ectopic activation stabilized the Hybrid phenotype. These perturbations were correlated with high overexpression in carcinomas supporting their role in carcinoma invasion. Further, the model-based analysis showed that a perturbation that mimics the SRC overexpression prevents the RPTP control, explaining the correlation between this alteration and cancer invasion. Moreover, the model-based analysis showed that cell-cell contacts that activate FAT4 in the case of a perturbation that mimics FAT4 overexpression modulate the transitions between Hybrid and Mesenchymal phenotype. In conclusion from this thesis, RPTP and FAT4 activation by cell-cell contacts are key microenvironment signals that are capable of controlling the transitions between Epithelial, Mesenchymal and Hybrid phenotype.