The mesenchymal-amoeboid transition (MAT) was proposed as a mechanism for cancer cells to adapt their migration mode to their environment. While the molecular pathways involved in this transition are well documented, the role of the microenvironment in the MAT is still poorly understood. Here, we investigated how confinement and adhesion affect this transition. We report that, in the absence of focal adhesions and under conditions of confinement, mesenchymal cells can spontaneously switch to a fast amoeboid migration phenotype. We identified two main types of fast migration--one involving a local protrusion and a second involving a myosin-II-dependent mechanical instability of the cell cortex that leads to a global cortical flow. Interestingly, transformed cells are more prone to adopt this fast migration mode. Finally, we propose a generic model that explains migration transitions and predicts a phase diagram of migration phenotypes based on three main control parameters: confinement, adhesion, and contractility.
IntroductionRegulatory T cells (Tregs) represent a critical barrier to immunotherapy of tumors. Established tumors suppress immune responses against their own antigens, and Tregs are emerging as a key mechanism contributing to this state of functional unresponsiveness. 1 In murine models, host Tregs become activated within days of tumor implantation. 2 Once activated, Tregs are difficult to eliminate and serve to potently and dominantly inhibit otherwise effective immune responses against the tumor. 3 We have shown that Foxp3 ϩ Tregs in the draining lymph nodes of mouse tumors become highly activated by exposure to the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). 4,5 In tumor-draining lymph nodes (TDLNs), IDO is expressed by a specific subset of IDO-competent plasmacytoid dendritic cells (DCs). 6 The combination of these IDO-expressing pDCs and IDO-activated Tregs renders the local milieu in the TDLNs profoundly inhibitory for T-cell activation. 7 Tregs can be suppressive, but this is not a fixed and immutable attribute. Resting Tregs are not spontaneously suppressive, and require an activation step before they become functionally inhibitory. 8 Conversely, the suppressive phenotype of Tregs is plastic. When Foxp3 is artificially ablated in mature Tregs, the suppressor phenotype is converted to a proinflammatory, T helper-like phenotype that can participate in autoimmunity. 9 Likewise, Tregs exposed to certain inflammatory signals (eg, from activated DCs or TLR ligands) can lose their suppressor activity 10 and may alter their phenotype (be "reprogrammed") to resemble proinflammatory effector cells. [11][12][13] Thus, at least in these experimental models, Tregs show a significant degree of phenotypic plasticity and are susceptible to both activation and deactivation (reprogramming) by signals from their local microenvironment.However, it is not known whether this apparent plasticity of Tregs is of biologic relevance for tumor immunology. In the current study, we test the hypothesis that, under conditions of antigendriven T-cell response to tumors, IDO functions as a critical molecular "switch" in TDLNs, regulating the phenotype and functional activity of Tregs. We show that, when IDO is active, Tregs are maintained in their normal potently suppressive state; but when IDO is blocked, Tregs undergo an inflammation-induced, interleukin-6 (IL-6)-dependent conversion into a nonsuppressive, proinflammatory phenotype similar to T-helper-17 (TH17) cells. These findings position IDO as a previously unsuspected key molecular regulator of Treg phenotype and function in TDLNs. Methods Reagents, cell lines, and mouse strainsA complete list of reagents, 1-methyl-D-tryptophan (1MT) preparation, tumor cell lines, and all transgenic and knockout mouse strains is given in supplemental materials (available on the Blood website; see the Supplemental Materials link at the top of the online article). Animal studies were approved by the Institutional Animal Care and Use Committee of the Medical College of Georgia. Detail...
Combined with backstepping techniques, an observer-based adaptive consensus tracking control strategy is developed for a class of high-order nonlinear multiagent systems, of which each follower agent is modeled in a semi-strict-feedback form. By constructing the neural network-based state observer for each follower, the proposed consensus control method solves the unmeasurable state problem of high-order nonlinear multiagent systems. The control algorithm can guarantee that all signals of the multiagent system are semi-globally uniformly ultimately bounded and all outputs can synchronously track a reference signal to a desired accuracy. A simulation example is carried out to further demonstrate the effectiveness of the proposed consensus control method.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.