When a collective outcome triggers a rare individual event: a mode of metastatic process in a cell population

A model of early metastatic process is based on the role of the protein PAI-1, which at high enough extracellular concentration promotes the transition of cancer cells to a state prone to migration. This transition is described at the single cell level as a bi-stable switch associated with a subcritical bifurcation. In a multilevel reaction-diffusion scenario, the microenvironment of the tumor is modified by the proliferating cell population so as to push the concentration of PAI-1 above the bifurcation threshold. The formulation in terms of partial differential equations fails to capture spatio-temporal heterogeneity. Cellular-automata and agent-based simulations of cell populations support the hypothesis that a randomly localized accumulation of PAI-1 can arise and trigger the escape of a few isolated cells. Far away from the primary tumor, these cells experience a reverse transition back to a proliferative state and could generate a secondary tumor. The proposed role of PAI-1 in controlling this metastatic cycle is candidate to explain its role in the progression of cancer

Matrix-Bound PAI-1 Supports Cell Blebbing via RhoA/ROCK1 Signaling

The microenvironment of a tumor can influence both the morphology and the behavior of cancer cells which, in turn, can rapidly adapt to environmental changes. Increasing evidence points to the involvement of amoeboid cell migration and thus of cell blebbing in the metastatic process; however, the cues that promote amoeboid cell behavior in physiological and pathological conditions have not yet been clearly identified. Plasminogen Activator Inhibitor type-1 (PAI-1) is found in high amount in the microenvironment of aggressive tumors and is considered as an independent marker of bad prognosis. Here we show by immunoblotting, activity assay and immunofluorescence that, in SW620 human colorectal cancer cells, matrix-associated PAI-1 plays a role in the cell behavior needed for amoeboid migration by maintaining cell blebbing, localizing PDK1 and ROCK1 at the cell membrane and maintaining the RhoA/ROCK1/MLC-P pathway activation. The results obtained by modeling PAI-1 deposition around tumors indicate that matrix-bound PAI-1 is heterogeneously distributed at the tumor periphery and that, at certain spots, the elevated concentrations of matrix-bound PAI-1 needed for cancer cells to undergo the mesenchymal-amoeboid transition can be observed. Matrix-bound PAI-1, as a matricellular protein, could thus represent one of the physiopathological requirements to support metastatic formation

PAI-1 and functional blockade of SNAI1 in breast cancer cell migration

12 pages, 5 figures.-- PMID: 19055748 [PubMed].-- et al.[Introduction]: Snail, a family of transcriptional repressors implicated in cell movement, has been correlated with tumour invasion. The Plasminogen Activation (PA) system, including urokinase plasminogen activator (uPA), its receptor and its inhibitor, plasminogen activator inhibitor type 1(PAI-1), also plays a key role in cancer invasion and metastasis, either through proteolytic degradation or by non-proteolytic modulation of cell adhesion and migration. Thus, Snail and the PA system are both over-expressed in cancer and influence this process. In this study we aimed to determine if the activity of SNAI1 (a member of the Snail family) is correlated with expression of the PA system components and how this correlation can influence tumoural cell migration.[Methods]: We compared the invasive breast cancer cell-line MDA-MB-231 expressing SNAI1 (MDA-mock) with its derived clone expressing a dominant-negative form of SNAI1 (SNAI1-DN). Expression of PA system mRNAs was analysed by cDNA microarrays and real-time quantitative RT-PCR. Wound healing assays were used to determine cell migration. PAI-1 distribution was assessed by immunostaining.[Results]: We demonstrated by both cDNA microarrays and realtime quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts. After performing an in vitro wound-healing assay, we observed that SNAI1-DN cells migrate more slowly than MDA-mock cells and in a more collective manner. The blockade of SNAI1 activity resulted in the redistribution of PAI-1 in SNAI1-DN cells decorating large lamellipodia, which are commonly found structures in these cells.[Conclusions]: In the absence of functional SNAI1, the expression of PAI-1 transcripts is decreased, although the protein is redistributed at the leading edge of migrating cells in a manner comparable with that seen in normal epithelial cells.This work was supported by the CNRS ACI Program "Complexité du vivant" (grant # 050009DR11) and by the Evry Genopole grant "Aide à l'acquisition d'équipement semi-lourd" 2007 and 2008.Peer reviewe

Etude de l'influence du PAI-1 matriciel sur la régulation de la transition Mésenchymo-Amiboïde des cellules cancéreuses

The Mesenchymal-Amoeboid transition (MAT) is required for metastatic escape, however it has not been associated with a precise physiopathological requirement yet. PAI-1, type-1 plasminogen activator inhibitor, is a tumor matrix molecule considered as marker of bad prognosis and found in high amount in the most aggressive tumors. We show that, in its activated matrix form, PAI-1 is able to maintain, in time and with concentration-dependence, the amoeboid morphology of colorectal and mammary cancer cells, and that this one is associated with a weak integrin-independant adhesion, an amoeboid migration and the activation of RhoA/ROCK-1/MLC-P pathway. The involved molecular mechanism has been partially underlined: we show that immobilization of PAI-1 and its link with uPA are essential, and we assume that the membrane receptor uPAR participates in the transmission of signals maintaining activated the RhoA/ROCK-1/MLC-P pathway. The compatibility of matrix PAI-1 effects towards the main signaling pathways involved in MAT regulation is established in silico with a method based on the modeling of interaction network dynamics. All this results enable for the first time to characterize a matrix physiopathological situation supporting MAT; and although the matrix form of PAI-1 has not been revealed all its secrets yet, it seems to be an interesting therapeutic target.La transition cellulaire Mésenchymo-Amiboïde (MAT) est requise pour l'échappement métastasique, cependant elle n'a encore jamais été associée à une situation physiopathologique précise. PAI-1, l'inhibiteur de l'activateur du plasminogène de type-1, est une molécule du microenvironnement tumoral considérée comme facteur de mauvais pronostic et localisée en forte concentration autour des tumeurs les plus invasives. Nous montrons que, sous sa forme matricielle active, PAI-1 est capable d'entretenir, au cours du temps et de façon dose-dépendante, la morphologie amiboïde de cellules cancéreuses colorectales et mammaires, et que celle-ci est associée à une adhérence faible intégrines-indépendante, une migration de type amiboïde et à l'activation de la voie RhoA/ROCK-1/MLC-P. Le mécanisme moléculaire mis en jeu a partiellement été mis en évidence : nous montrons que l'immobilisation de PAI-1 et sa liaison à l'uPA sont indispensables, et nous suggérons la possibilité que le récepteur membranaire uPAR participe à la transmission de signaux maintenant la voie RhoA/ROCK-1/MLC-P active. La compatibilité des effets du PAI-1 matriciel vis-à-vis des principales voies de signalisation impliquées dans la régulation de la transition MAT est établie in silico grâce à une méthode fondée sur la modélisation de la dynamique des réseaux d'interactions. L'ensemble de ces résultats permet pour la première fois de caractériser une situation physiopathologique microenvironnementale favorable à la transition MAT ; et bien que la forme matricielle de PAI-1 n'ait pas encore livré tous ses secrets, elle semble être une cible thérapeutique intéressante

Study on the influence of matrix PAI-1 on the regulation of Mesenchymal-Amoeboid transition of cancer cells

La transition cellulaire Mésenchymo-Amiboïde (MAT) est requise pour l’échappement métastasique, cependant elle n’a encore jamais été associée à une situation physiopathologique précise. PAI-1, l’inhibiteur de l’activateur du plasminogène de type-1, est une molécule du microenvironnement tumoral considérée comme facteur de mauvais pronostic et localisée en forte concentration autour des tumeurs les plus invasives. Nous montrons que, sous sa forme matricielle active, PAI-1 est capable d’entretenir, au cours du temps et de façon dose-dépendante, la morphologie amiboïde de cellules cancéreuses colorectales et mammaires, et que celle-ci est associée à une adhérence faible intégrines-indépendante, une migration de type amiboïde et à l’activation de la voie RhoA/ROCK-1/MLC-P. Le mécanisme moléculaire mis en jeu a partiellement été mis en évidence : nous montrons que l’immobilisation de PAI-1 et sa liaison à l’uPA sont indispensables, et nous suggérons la possibilité que le récepteur membranaire uPAR participe à la transmission de signaux maintenant la voie RhoA/ROCK-1/MLC-P active. La compatibilité des effets du PAI-1 matriciel vis-à-vis des principales voies de signalisation impliquées dans la régulation de la transition MAT est établie in silico grâce à une méthode fondée sur la modélisation de la dynamique des réseaux d’interactions. L’ensemble de ces résultats permet pour la première fois de caractériser une situation physiopathologique microenvironnementale favorable à la transition MAT ; et bien que la forme matricielle de PAI-1 n’ait pas encore livré tous ses secrets, elle semble être une cible thérapeutique intéressante.The Mesenchymal-Amoeboid transition (MAT) is required for metastatic escape, however it has not been associated with a precise physiopathological requirement yet. PAI-1, type-1 plasminogen activator inhibitor, is a tumor matrix molecule considered as marker of bad prognosis and found in high amount in the most aggressive tumors. We show that, in its activated matrix form, PAI-1 is able to maintain, in time and with concentration-dependence, the amoeboid morphology of colorectal and mammary cancer cells, and that this one is associated with a weak integrin-independant adhesion, an amoeboid migration and the activation of RhoA/ROCK-1/MLC-P pathway. The involved molecular mechanism has been partially underlined: we show that immobilization of PAI-1 and its link with uPA are essential, and we assume that the membrane receptor uPAR participates in the transmission of signals maintaining activated the RhoA/ROCK-1/MLC-P pathway. The compatibility of matrix PAI-1 effects towards the main signaling pathways involved in MAT regulation is established in silico with a method based on the modeling of interaction network dynamics. All this results enable for the first time to characterize a matrix physiopathological situation supporting MAT; and although the matrix form of PAI-1 has not been revealed all its secrets yet, it seems to be an interesting therapeutic target

Discrete causal model view of biological networks

International audienceSignaling and regulatory pathways coordinate multiple cellular functions in response to environmental variations. Discovering the pathways governing functionally specific responses is essential for understanding of biological systems. It aims at determining the causal cascades of regulations leading to the observed responses. Their characterization by computational methods remains an important and challenging question. The presented cabin (Causal Analysis of Biological Interaction Network) method determines a causal model view composed of a subnetwork and a set of agent states deduced from observations with regards to a model of network dynamics. The validity of the results is ensured by formally checking the conditions of correctness of a model with respect to observations. State-based and symbolic versions of the algorithm have been implemented and used for a biological case study

Etude de l'influence du PAI-1 matriciel sur la régulation de la transition Mésenchymo-Amiboïde des cellules cancéreuses

La transition cellulaire Mésenchymo-Amiboïde (MAT) est requise pour l échappement métastasique, cependant elle n a encore jamais été associée à une situation physiopathologique précise. PAI-1, l inhibiteur de l activateur du plasminogène de type-1, est une molécule du microenvironnement tumoral considérée comme facteur de mauvais pronostic et localisée en forte concentration autour des tumeurs les plus invasives. Nous montrons que, sous sa forme matricielle active, PAI-1 est capable d entretenir, au cours du temps et de façon dose-dépendante, la morphologie amiboïde de cellules cancéreuses colorectales et mammaires, et que celle-ci est associée à une adhérence faible intégrines-indépendante, une migration de type amiboïde et à l activation de la voie RhoA/ROCK-1/MLC-P. Le mécanisme moléculaire mis en jeu a partiellement été mis en évidence : nous montrons que l immobilisation de PAI-1 et sa liaison à l uPA sont indispensables, et nous suggérons la possibilité que le récepteur membranaire uPAR participe à la transmission de signaux maintenant la voie RhoA/ROCK-1/MLC-P active. La compatibilité des effets du PAI-1 matriciel vis-à-vis des principales voies de signalisation impliquées dans la régulation de la transition MAT est établie in silico grâce à une méthode fondée sur la modélisation de la dynamique des réseaux d interactions. L ensemble de ces résultats permet pour la première fois de caractériser une situation physiopathologique microenvironnementale favorable à la transition MAT; et bien que la forme matricielle de PAI-1 n ait pas encore livré tous ses secrets, elle semble être une cible thérapeutique intéressante.The Mesenchymal-Amoeboid transition (MAT) is required for metastatic escape, however it has not been associated with a precise physiopathological requirement yet. PAI-1, type-1 plasminogen activator inhibitor, is a tumor matrix molecule considered as marker of bad prognosis and found in high amount in the most aggressive tumors. We show that, in its activated matrix form, PAI-1 is able to maintain, in time and with concentration-dependence, the amoeboid morphology of colorectal and mammary cancer cells, and that this one is associated with a weak integrin-independant adhesion, an amoeboid migration and the activation of RhoA/ROCK-1/MLC-P pathway. The involved molecular mechanism has been partially underlined: we show that immobilization of PAI-1 and its link with uPA are essential, and we assume that the membrane receptor uPAR participates in the transmission of signals maintaining activated the RhoA/ROCK-1/MLC-P pathway. The compatibility of matrix PAI-1 effects towards the main signaling pathways involved in MAT regulation is established in silico with a method based on the modeling of interaction network dynamics. All this results enable for the first time to characterize a matrix physiopathological situation supporting MAT; and although the matrix form of PAI-1 has not been revealed all its secrets yet, it seems to be an interesting therapeutic target.EVRY-Bib. électronique (912289901) / SudocSudocFranceF

Dynamique du microenvironnement cellulaire

National audienc

When a collective outcome triggers a rare individual event: a mode of metastatic process in a cell population

A model of early metastatic process is based on the role of the protein PAI-1, which at high enough extracellular concentration promotes the transition of cancer cells to a state prone to migration. This transition is described at the single cell level as a bi-stable switch associated with a subcritical bifurcation. In a multilevel reaction-diffusion scenario, the microenvironment of the tumor is modified by the proliferating cell population so as to push the concentration of PAI-1 above the bifurcation threshold. The formulation in terms of partial differential equations fails to capture spatio-temporal heterogeneity. Cellular-automata and agent-based simulations of cell populations support the hypothesis that a randomly localized accumulation of PAI-1 can arise and trigger the escape of a few isolated cells. Far away from the primary tumor, these cells experience a reverse transition back to a proliferative state and could generate a secondary tumor. The proposed role of PAI-1 in controlling this metastatic cycle is candidate to explain its role in the progression of cancer

When a Collective Outcome Triggers a Rare Individual Event: A Mode of Metastatic Process in a Cell Population

A model of early metastatic process is based on the role of the protein PAI-1, which at high enough extracellular concentration promotes the transition of cancer cells to a state prone to migration. This transition is described at the single cell level as a bi-stable switch associated with a subcritical bifurcation. In a multilevel reaction-diffusion scenario, the micro-environment of the tumor is modified by the proliferating cell population so as to push the concentration of PAI-1 above the bifurcation threshold. The formulation in terms of partial differential equations fails to capture spatio-temporal heterogeneity. Cellular-automata and agent-based simulations of cell populations support the hypothesis that a randomly localized accumulation of PAI-1 can arise and trigger the escape of a few isolated cells. Far away from the primary tumor, these cells experience a reverse transition back to a proliferative state and could generate a secondary tumor. The suggested role of PAI-1 in controlling this metastatic cycle is candidate to explain its role in the progression of cancer.agent-based simulation, cell population, metastastic escape, multilevel model, multistability, reaction-diffusion,