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Cell fate decision

Logical modelling of myelofibrotic microenvironment predicts dysregulated progenitor stem cell crosstalk


Idiopathic primary myelofibrosis is an age-related clonal neoplastic disorder of
haematopoiesis characterised by a myeloproliferation and myelofibrosis. Recent
evidence suggests that disease onset results from an altered bone marrow
microenvironment, leading to disrupted crosstalk between progenitor haematopoietic
and mesenchymal stem cells populations. 90% of myelofibrosis cases exhibit ectopic
mutations of JAK2, CALR and, or MPL genes which all converge on the activation of
JAK and STAT signaling pathways. Treatments aiming to target STAT overactivity
have been developed; however, disease management is conducted at advanced
stages of the disease and treatments are not effective. A computational description
of how altered microenvironments can lead to dysregulated crosstalk between
haematopoietic and mesenchymal stem cells populations following STAT activation
would increase our knowledge of disease pathology and influence future treatment
protocols. To meet this aim, we have constructed a logical model that accounts for
the myelofibrotic microenvironment following TPO and lTLR signalling, integrated
with JAK-STAT signalling. The model primarily aims to provide a mechanistic
understanding of the dysregulated crosstalk between progenitor HSC’s, MSC’s and
the microenvironment to predict the onset of PMF with, and without the JAK
activation. Wildtype simulations result in 4 cyclic attractors being obtained, all
depending on combination of inputs being modelled. The model predicted that
presence of TPO and lTLR signalling are both required to facilitate disease onset for
wildtype simulations. For simulations involving JAK knock-in mutated scenarios, the
model resulted in 4 fixed point attractors, with the presence of lTLR alone being
sufficient to drive disease progression.

Pedro Monteiro

Control of proliferation by oncogenes and tumor suppressors


This model is an illustrative example of a signal transduction network
relevant to a cancer hallmark phenotype, uncontrolled proliferation. In
the normal context cell proliferation is driven by growth factors that
bind to receptor tyrosine kinases (RTKs); yet it can also be an outcome
of alterations in signal transduction proteins. Six separate pathways
are typically pointed out in biological literature. This model includes
all of these pathways in a single network. The unperturbed system has
two possible steady states, a non-proliferative one and one with
controlled proliferation (Proliferation = 1), among which it may select
depending on environmental signals. Alterations in certain oncogenes or
tumor suppressor genes yield a single outcome: uncontrolled
proliferation (Proliferation = 2). Targeted inhibition of an oncogene
(here, PI3K) may not eliminate the proliferating phenotype.

Aurelien Naldi

Cell-Fate Decision in Response to Death Receptor Engagement


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].


Laurence Calzone
Related references

HSPCs-MSCs. Communication pathways between Hematopoietic Stem Progenitor Cells (HSPCs) and Mesenchymal Stromal Cells (MSCs)


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.

C. Chaouiya (with J. Enciso)

Mutually exclusive and co-occurring genetic alterations in bladder tumorigenesis


Relationships between genetic alterations, such as co-occurrence or mutual exclusivity, are often observed in cancer, where their understanding may provide new insights into etiology and clinical management. In this study, we combined statistical analyses and computational modelling to explain patterns of genetic alterations seen in 178 patients with bladder tumours (either muscle-invasive or non-muscle-invasive). A statistical analysis on frequently altered genes identified pair associations including co-occurrence or mutual exclusivity. Focusing on genetic alterations of protein-coding genes involved in growth factor receptor signalling, cell cycle and apoptosis entry, we complemented this analysis with a literature search to focus on nine pairs of genetic alterations of our dataset, with subsequent verification in three other datasets available publically. To understand the reasons and contexts of these patterns of associations while accounting for the dynamics of associated signalling pathways, we built a logical model. This model was validated first on published mutant mice data, then used to study patterns and to draw conclusions on counter-intuitive observations, allowing one to formulate predictions about conditions where combining genetic alterations benefits tumorigenesis. For example, while CDKN2A homozygous deletions occur in a context of FGFR3 activating mutations, our model suggests that additional PIK3CA mutation or p21CIP deletion would greatly favour invasiveness. Further, the model sheds light on the temporal orders of gene alterations, for example, showing how mutual exclusivity of FGFR3 and TP53 mutations is interpretable if FGFR3 is mutated first. Overall, our work shows how to predict combinations of the major gene alterations leading to invasiveness.

Claudine Chaouiya

Senescence onset at the G1/S cell cycle checkpoint


DNA damage (single or double-strand breaks) triggers adapted cellular responses. These responses are elicited through signalling pathways, which activate cell cycle checkpoints and basically lead to three cellular fates: cycle arrest promoting DNA repair, senescence (permanent arrest) or cell death. Cellular senescence is known for having a tumour-suppressive function and its regulation arouses a growing scientific interest. Here, we advance a qualitative model covering DNA damage response pathways, focusing on G1/S checkpoint enforcement, supposedly more sensitive to arrest than G2/M checkpoint.

We define a discrete, logical model encompassing ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) pathways activation upon DNA damage, as well as G1/S checkpoint main components. It also includes the stress responsive protein p38MAPK (mitogen-activated protein kinase 14) known to be involved in the regulation of senescence. The model has four outcomes that convey alternative cell fates: proliferation, (transient) cell cycle arrest, apoptosis and senescence. Different levels of DNA damage are considered, defined by distinct combinations of single and double-strand breaks. Each leads to a single stable state denoting the cell fate adopted upon this specific damage. A range of model perturbations corresponding to gene loss-of-function or gain-of-function is compared to experimental mutations.

As a step towards an integrative model of DNA-damage response pathways to better cover the onset of senescence, our model focuses on G1/S checkpoint enforcement. This model qualitatively agrees with most experimental observations, including experiments involving mutations. Furthermore, it provides some predictions.

C. Chaouiya

Network model of survival signaling in large granular lymphocyte leukemia (Zhang et al 2008)


Zhang et al. defined a logical model of the T-LGL survival signaling network to investigate the signaling components that determine the survival of CTL in T-LGL leukemia. Please refer to the supporting publication [1].


  1. Zhang R, Shah MV, Yang J, Nyland SB, Liu X, Yun JK, Albert R, Loughran TP.  2008.  Network model of survival signaling in large granular lymphocyte leukemia.. Proceedings of the National Academy of Sciences of the United States of America. 105(42):16308-13.
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