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Modeling TGF-? in early stages of cancer tissue dynamics.

ABSTRACT: Recent works have highlighted a double role for the Transforming Growth Factor ? (TGF-?): it inhibits cancer in healthy cells and potentiates tumor progression during late stage of tumorigenicity, respectively; therefore it has been termed the "Jekyll and Hyde" of cancer or, alternatively, an "excellent servant but a bad master". It remains unclear how this molecule could have the two opposite behaviours. In this work, we propose a TGF-? multi scale mathematical model at molecular, cellular and tissue scales. The multi scalar behaviours of the TGF-? are described by three coupled models built up together which can approximatively be related to distinct microscopic, mesoscopic, and macroscopic scales, respectively. We first model the dynamics of TGF-? at the single-cell level by taking into account the intracellular and extracellular balance and the autocrine and paracrine behaviour of TGF-?. Then we use the average estimates of the TGF-? from the first model to understand its dynamics in a model of duct breast tissue. Although the cellular model and the tissue model describe phenomena at different time scales, their cumulative dynamics explain the changes in the role of TGF-? in the progression from healthy to pre-tumoral to cancer. We estimate various parameters by using available gene expression datasets. Despite the fact that our model does not describe an explicit tissue geometry, it provides quantitative inference on the stage and progression of breast cancer tissue invasion that could be compared with epidemiological data in literature. Finally in the last model, we investigated the invasion of breast cancer cells in the bone niches and the subsequent disregulation of bone remodeling processes. The bone model provides an effective description of the bone dynamics in healthy and early stages cancer conditions and offers an evolutionary ecological perspective of the dynamics of the competition between cancer and healthy cells.

SUBMITTER: Ascolani G

PROVIDER: S-EPMC3930754 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Modeling TGF-β in early stages of cancer tissue dynamics.

Ascolani Gianluca G Liò Pietro P

PloS one 20140220 2

Recent works have highlighted a double role for the Transforming Growth Factor β (TGF-β): it inhibits cancer in healthy cells and potentiates tumor progression during late stage of tumorigenicity, respectively; therefore it has been termed the "Jekyll and Hyde" of cancer or, alternatively, an "excellent servant but a bad master". It remains unclear how this molecule could have the two opposite behaviours. In this work, we propose a TGF-β multi scale mathematical model at molecular, cellular and ...[more]

PMID: 24586338

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Project description:The formation of sensory organs is an important developmental and evolutionary question. In the context of regenerative medicine also, it is important to know as accurately as possible how sensory organs form. The formation of ears, eyes or nose stems presumably from tissue thickenings called placodes Graham and Shimeld (J Anat 222(1):32-40, 2013), Horie et al. (Nature 560:228-232, 2018) which become these organs after processes termed inductions. However, the origin of the placodes, the mechanism of induction and the overall face organization are not understood. Recently, it has been suggested that there is a physical principle to face organization. Indeed, it has been shown that there exists a pattern of rings and rays in the early blastula which defines the position of face landmarks, especially the ears and eyes Fleury et al. (Second order division in sectors as a prepattern for sensory organs in vertebrate development, 2021), Fleury and Abourachid (Eu Phys J E 45:31, 2022). Tensions in the sectors defined by the intersections of the said rings and rays create the actual face features. I report here that a similar situation exists for the nose. This explains the robustness of face formation in the chordates phylum. By studying nasal pit formation in the chicken embryo by time-lapse (T-L) video microscopy, I show that the nasal placode originates in a narrow sector deformed by tension forces following the biaxial pattern of rings and rays mentioned above. Cells align in the pattern and exert organized forces. Further contractions of the pattern contribute to inducing the nasal pit. The observation of the early pre-pattern of lines which locks the facial features explains readily a number of facts regarding sensory organs. Especially the existence of a lacrimal canal between the eye and the nose Lefevre and Freitag (Semin Ophthalmo l 27(5-6):175-86, 2012), or of a slit connecting the nose to the mouth, the correlation between nose, mouth and eye morphogenesis Dubourg et al. (J Rare Dis 2(8), 2007), the presence of shallow valleys on the nasal and optic vesicles, the medio-lateral asymmetry of nostrils with often a bent slit Liu et al. (PLoS ONE 12: e0181928, 2017), the uneven number of nostrils in many fish Cox (J R Soc Interf 5(23):575-593, 2008) and possibly the transition between agnatha and gnathostomes Gai and Zhu (Chinese Sci Bull 57(31), 2012): all appear under this light, geometrically straightforward. The nasal pit forms in a sector of tissue which was present on the blastodic (early embryonic stage), and which is projected onto the nasal vesicle during neurulation. The nasal pit forms along a hairpin of tissue. The top part of the hairpin forms the nares, and the bottom part a groove often visible in many animals.

Project description:Diagnosis and management of bone and joint infections (BJI) is a challenging task. The high intra and inter patient's variability in terms of clinical presentation makes it impossible to rely on a systematic description or classical statistical analysis for its diagnosis. Advances can be achieved through a better understanding of the system behavior that results from the interactions between the components at a micro-scale level, which is difficult to mastered using traditional methods. Multiple studies from the literature report factors and interactions that affect the dynamics of the BJI system. The objectives of this study were (i) to perform a systematic review to identify relevant interactions between agents (cells, pathogens) and parameters values that characterize agents and interactions, and (ii) to develop a two dimensional computational model of the BJI system based on the results of the systematic review. The model would simulate the behavior resulting from the interactions on the cellular and molecular levels to explore the BJI dynamics, using an agent-based modeling approach. The BJI system's response to different microbial inoculum levels was simulated. The model succeeded in mimicking the dynamics of bacteria, the innate immune cells, and the bone mass during the first stage of infection and for different inoculum levels in a consistent manner. The simulation displayed the destruction in bone tissue as a result of the alteration in bone remodeling process during the infection. The model was used to generate different patterns of system behaviors that could be analyzed in further steps. Simulations results suggested evidence for the existence of latent infections. Finally, we presented a way to analyze and synthesize massive simulated data in a concise and comprehensive manner based on the semi-supervised identification of ordinary differential equations (ODE) systems. It allows to use the known framework for temporal and structural ODE analyses and therefore summarize the whole simulated system dynamical behavior. This first model is intended to be validated by in vivo or in vitro data and expected to generate hypotheses to be challenged by real data. Step by step, it can be modified and complexified based on the test/validation iteration cycles.

Project description:Transforming growth factor-β1, -β2, and -β3 (TGF-β1, -β2, and -β3) are secreted signaling ligands that play essential roles in tissue development, tissue maintenance, immune response, and wound healing. TGF-β ligands form homodimers and signal by assembling a heterotetrameric receptor complex comprised of two type I receptor (TβRI):type II receptor (TβRII) pairs. TGF-β1 and TGF-β3 ligands signal with high potency due to their high affinity for TβRII, which engenders high-affinity binding of TβRI through a composite TGF-β:TβRII binding interface. However, TGF-β2 binds TβRII 200-500 more weakly than TGF-β1 and TGF-β3 and signals with lower potency compared with these ligands. Remarkably, the presence of an additional membrane-bound coreceptor, known as betaglycan, increases TGF-β2 signaling potency to levels similar to TGF-β1 and -β3. The mediating effect of betaglycan occurs even though it is displaced from and not present in the heterotetrameric receptor complex through which TGF-β2 signals. Published biophysics studies have experimentally established the kinetic rates of the individual ligand-receptor and receptor-receptor interactions that initiate heterotetrameric receptor complex assembly and signaling in the TGF-β system; however, current experimental approaches are not able to directly measure kinetic rates for the intermediate and latter steps of assembly. To characterize these steps in the TGF-β system and determine the mechanism of betaglycan in the potentiation of TGF-β2 signaling, we developed deterministic computational models with different modes of betaglycan binding and varying cooperativity between receptor subtypes. The models identified conditions for selective enhancement of TGF-β2 signaling. The models provide support for additional receptor binding cooperativity that has been hypothesized but not evaluated in the literature. The models further showed that betaglycan binding to the TGF-β2 ligand through two domains provides an effective mechanism for transfer to the signaling receptors that has been tuned to efficiently promote assembly of the TGF-β2(TβRII)2(TβRI)2 signaling complex.

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Modeling TGF-? in early stages of cancer tissue dynamics.

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Modeling TGF-β in early stages of cancer tissue dynamics.

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