Mammal

Epithelial to Mesenchymal Transition (EMT) has been associated with cancer cell heterogeneity, plasticity and metastasis. However, the extrinsic signals supervising these phenotypic transitions remain elusive. To identify microenvironmental signals controlling cancer-associated phenotypes amid the EMT continuum, we defined a logical model of the EMT cellular network that access the qualitative degrees of cell adhesions by adherent junctions and focal adhesions, two features affected during EMT. Model attractors could recover epithelial, mesenchymal and hybrid phenotypes. In silico simulations provided evidences that hybrid phenotypes may arise through independent molecular paths, involving stringent extrinsic signals. Of particular interest, model predictions and their experimental validations indicated that: 1) ECM stiffening is a prerequisite for cells overactivating FAK-SRC to upregulate SNAIL1 and acquire a mesenchymal phenotype, and 2) FAK-SRC inhibition of cell-cell contacts through the Receptor Protein Tyrosine Phosphates kappa leads to the acquisition of a full mesenchymal rather than a hybrid phenotype. Altogether, our computational and experimental approaches permitted to identify critical microenvironmental signals controlling hybrid EMT phenotypes, and indicated that EMT involves multiple molecular programs.

This model provides a generic high-level view of the interplays between NFκB pro-survival pathway, RIP1-dependent necrosis, and the apoptosis pathway in response to death receptor-mediated signals.

Wild type simulations demonstrate robust segregation of cellular responses to receptor engagement. Model simulations recapitulate documented phenotypes of protein knockdowns and enable the prediction of the effects of novel knockdowns. In silico experiments simulate the outcomes following ligand removal at different stages, and suggest experimental approaches to further validate and specialise the model for particular cell types.

This analysis gives specific predictions regarding cross-talks between the three pathways, as well as the transient role of RIP1 protein in necrosis, and confirms the phenotypes of novel perturbations. Our wild type and mutant simulations provide novel insights to restore apoptosis in defective cells. The model analysis expands our understanding of how cell fate decision is made.

The original model focuses on the interplay between three pathways activated in response to the same signal [1].

This model has then been adapted for multiscale analysis [2].

References

This model is a refined version of the logical model of the p53-mdm2 network described in Fig. 5a of Abou-Jaoudé et al. [1].

The regulatory graph describes the interactions between protein p53, the ubiquitin ligase Mdm2 in its nuclear and cytoplasmic forms, and DNA damage. It relies on biological data taken from literature.

In short, the nuclear component of Mdm2 down-regulates the level of active p53. This occurs both by accelerating p53 degradation through ubiquitination and by blocking the transcriptional activity of p53.

Protein p53 plays a dual role. It activates the expression of Mdm2 thereby up-regulating the level of cytoplasmic Mdm2, and down-regulates the level of nuclear Mdm2 by inhibiting Mdm2 nuclear translocation through inactivation of the kinase Akt.

DNA damage has a negative influence on the level of nuclear Mdm2, by accelerating its degradation through ATM-mediated phosphorylation and auto-ubiquitination.

Damage-induced Mdm2 destabilization enables p53 to accumulate and remain active.

Finally, high levels of p53 promote damage repair by inducing the synthesis of DNA repair proteins.

References

Blood cells are derived from a common set of hematopoietic stem cells, which differentiate into more specific progenitors of the myeloid and lymphoid lineages, ultimately leading to differentiated cells. This developmental process is controlled by a complex regulatory network involving cytokines and their receptors, transcription factors and chromatin remodelers.
Based on public and novel data from molecular genetic experiments (qPCR, western blots, EMSA), along with genome-wide assays (RNA-seq, ChIP-seq), we defined a logical model recapitulating cytokine-induced differentiation of common progenitors, the effect of various reported gene knock-downs, as well as reprogramming of pre-B cells into macrophages induced by ectopic expression of specific transcription factors.

Note: This model is also available at BioModels database BioModels ID: 1610240000.

Lineage fate decisions of hematopoietic cells depend on intrinsic factors and extrinsic signals provided by the bone marrow microenvironment, where they reside. Abnormalities in composition and function of hematopoietic niches have been proposed as key contributors of acute lymphoblastic leukemia(ALL) progression. Our previous experimental findings strongly suggest that pro-inflammatory cues contribute to mesenchymal niche abnormalities that result in maintenance of ALL precursor cells at the expense of normal hematopoiesis. Here, we propose a molecular regulatory network interconnecting the major communication pathways between hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs) within the bone marrow. Dynamical analysis of the network as a Boolean model reveals two stationary states that can be interpreted as the intercellular contact status.
Furthermore, simulations describe the molecular patterns observed during experimental proliferation and activation. Importantly, our model predicts instability in the CXCR4/CXCL12 and VLA4/VCAM1 interactions following microenvironmental perturbation due by temporal signaling from Toll like receptors (TLRs) ligation. Therefore, aberrant expression of NF-κB induced by intrinsic or extrinsic factors may contribute to create a tumor microenvironment where a negative feedback loop inhibiting CXCR4/CXCL12 and VLA4/VCAM1 cellular communication axes allows for the maintenance of malignant cells.