The Experts below are selected from a list of 1221 Experts worldwide ranked by ideXlab platform
Madeleine J Oudin - One of the best experts on this subject based on the ideXlab platform.
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tumor cell driven extracellular matrix remodeling drives Haptotaxis during metastatic progression
Cancer Discovery, 2016Co-Authors: Madeleine J Oudin, Sreeja B. Asokan, Tatsiana Kosciuk, Oliver Jonas, Liliane C Broye, Bruna C Guido, Jeffrey Wyckoff, Daisy N Riquelme, John M Lamar, Charles A WhittakerAbstract:Fibronectin (FN) is a major component of the tumor microenvironment, but its role in promoting metastasis is incompletely understood. Here, we show that FN gradients elicit directional movement of breast cancer cells, in vitro and in vivo . Haptotaxis on FN gradients requires direct interaction between α5β1 integrin and MENA, an actin regulator, and involves increases in focal complex signaling and tumor cell–mediated extracellular matrix (ECM) remodeling. Compared with MENA, higher levels of the prometastatic MENAINV isoform associate with α5, which enables 3-D Haptotaxis of tumor cells toward the high FN concentrations typically present in perivascular space and in the periphery of breast tumor tissue. MENAINV and FN levels were correlated in two breast cancer cohorts, and high levels of MENAINV were significantly associated with increased tumor recurrence as well as decreased patient survival. Our results identify a novel tumor cell–intrinsic mechanism that promotes metastasis through ECM remodeling and ECM-guided directional migration. Significance: Here, we provide new insight into how tumor cell:ECM interactions generate signals and structures that promote directed tumor cell migration, a critical component of metastasis. Our results identify a tumor cell–intrinsic mechanism driven by the actin regulatory protein MENA that promotes ECM remodeling and Haptotaxis along FN gradients. Cancer Discov; 6(5); 516–31. ©2016 AACR. See related commentary by Santiago-Medina and Yang, [p. 474][1] . This article is highlighted in the In This Issue feature, [p. 461][2] [1]: /lookup/volpage/6/474?iss=5 [2]: /lookup/volpage/6/461?iss=5
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abstract 5057 mena at the nexus of chemotaxis and Haptotaxis during tumor progression
Cancer Research, 2015Co-Authors: Madeleine J Oudin, Miles A Miller, Tatsiana Kosciuk, Joelle Klazen, Alisha Lussiez, Douglas A Lauffenburger, James E Bear, Frank B GertlerAbstract:Directed-cell migration is key step in the metastatic cascade, and multiple cues can promote local invasion. The most well studied mode of cell motility for metastasizing tumor cells is chemotaxis, the directional movement of cells attracted to a source of soluble cues. In contrast, Haptotaxis, migration of cells on gradients of substrate-bound factors, remains poorly understood. Mena, an actin regulatory protein, plays an important role in cell motility and is upregulated in various cancers, driving migration in response to chemotactic and haptotactic cues. We have recently shown expression of the pro-metastatic isoform of Mena, MenaINV, increases sensitivity to growth factors (EGF, HGF and IGF) via dysregulation of the phosphatase PTP1B, as well as high concentrations of fibronectin (FN) via its interaction with the integrin α5β1. We hypothesized that MenaINV may also promote crosstalk between these two pathways to drive metastasis. First, we show that MenaINV-driven Haptotaxis on FN gradients and FN-driven invasion requires crosstalk between α5β1 and EGFR. Indeed, we show evidence that MenaINV expression is associated high phosphorylation of EGFR in high FN environments in vitro and in human breast cancer databases. Second, we find that MenaINV promotes synergy between EGF and FN in vitro and in vivo, leading to hyper-invasive phenotypes that drive more invasion than which each cue alone. Finally, we show that MenaINV-driven Haptotaxis, ECM reorganization and 3D invasion requires RCP-dependent recycling of α5β1 and EGFR. Together, our data demonstrate that MenaINV is a shared component of the machinery that mediates both haptotactic responses to FN and chemotactic responses to EGF, two pathways that promote tumor progression. Citation Format: Madeleine J. Oudin, Miles A. Miller, Tatsiana Kosciuk, Joelle Klazen, Alisha Lussiez, Douglas Lauffenburger, James E. Bear, Frank B. Gertler. Mena at the nexus of chemotaxis and Haptotaxis during tumor progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5057.
Youshan Tao - One of the best experts on this subject based on the ideXlab platform.
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global classical solutions to a doubly haptotactic cross diffusion system modeling oncolytic virotherapy
Journal of Differential Equations, 2020Co-Authors: Youshan Tao, Michael WinklerAbstract:Abstract This work studies a Haptotaxis system proposed as a model for oncolytic virotherapy, accounting for interaction between uninfected cancer cells, infected cancer cells, extracellular matrix (ECM) and oncolytic virus. In addition to random movement, both uninfected and infected tumor cells migrate haptotactically toward higher ECM densities; moreover, besides degrading the non-diffusible ECM upon contact the two cancer cell populations are subject to an infection-induced transition mechanism driven by virus particles which are released by infected cancer cells, and which assault the uninfected part of the tumor. The main results assert global classical solvability in an associated initial-boundary value problem posed in one- or two-dimensional domains with any given suitably regular initial data. This is achieved by discovering a quasi-Lyapunov functional structure that allows to appropriately cope with the presence of nonlinear zero-order interaction terms which apparently form the most significant additional mathematical challenge of the considered system in comparison to previously studied Haptotaxis models.
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Global Solution to a Model of Tumor Invasion
2020Co-Authors: Youshan Tao, Guo ZhuAbstract:Abstract. This paper deals with a mathematical model which is used to investigate the role of extracellular matrix (ECM) concentration in tumor cell invasion. The model is a system of partial differential equations governing tumor cell density, the tumor cell-derived protease concentration and the collagen gel concentration. In this system, the equation describing the evolution of the tumor cell density is a diffusion-Haptotaxis parabolic equation. For general haptotactic coefficient, the global existence of solutions for this model is proved. The proof is based on a priori estimates, together with the L p estimates and the Schauder estimates of parabolic equations. Mathematics Subject Classification: 22E46; 35R35; 53C3
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boundedness in a two dimensional chemotaxis Haptotaxis system
arXiv: Analysis of PDEs, 2014Co-Authors: Youshan TaoAbstract:This work studies the chemotaxis-Haptotaxis system $$\left\{ \begin{array}{ll} u_t= \Delta u - \chi \nabla \cdot (u\nabla v) - \xi \nabla \cdot (u\nabla w) + \mu u(1-u-w), &\qquad x\in \Omega, \, t>0, \\[1mm] v_t=\Delta v-v+u, &\qquad x\in \Omega, \, t>0, \\[1mm] w_t=-vw, &\qquad x\in \Omega, \, t>0, \end{array} \right. $$ in a bounded smooth domain $\Omega\subset\mathbb{R}^2$ with zero-flux boundary conditions, where the parameters $\chi, \xi$ and $\mu$ are assumed to be positive. It is shown that under appropriate regularity assumption on the initial data $(u_0, v_0, w_0)$, the corresponding initial-boundary problem possesses a unique classical solution which is global in time and bounded. In addition to coupled estimate techniques, a novel ingredient in the proof is to establish a one-sided pointwise estimate, which connects $\Delta w$ to $v$ and thereby enables us to derive useful energy-type inequalities that bypass $w$. However, we note that the approach developed in this paper seems to be confined to the two-dimensional setting.
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dominance of chemotaxis in a chemotaxis Haptotaxis model
Nonlinearity, 2014Co-Authors: Youshan Tao, Michael WinklerAbstract:This paper deals with the Neumann problem for the coupled chemotaxis–Haptotaxis model of cancer invasion given byfor x ∈ Ω and t > 0 with, respectively, given nonnegative initial data u0 and w0, where χ, ξ and μ are positive parameters, Ω is a bounded domain in , and n ≥ 1, with smooth boundary.The goal of this work is to identify two parallels between the solution behaviour in () and that in the corresponding two-component chemotaxis system obtained when w ≡ 0:• For the latter, it has been known that for any choice of , solutions are global and remain bounded under the conditionThe first result of this paper says that the above statement remains true for arbitrarily large haptotactic ingredients: If () holds, then for any ξ > 0 and all reasonably smooth w0, () possesses a globally defined solution which is bounded in each of its components.• With regard to the qualitative solution behaviour, this work identifies an explicit smallness condition on w0 which under the assumption () asserts exponential decay of w in the large time limit, whereas both u and v persist in a certain sense.
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Global existence for a Haptotaxis model of cancer invasion with tissue remodeling
Nonlinear Analysis: Real World Applications, 2011Co-Authors: Youshan TaoAbstract:Abstract This paper considers a 3×3 Haptotaxis model of cancer invasion with tissue remodeling. The model consists of a parabolic Haptotaxis partial differential equation (PDE) describing the evolution of tumor cell density, an ordinary differential equation modeling the proteolysis and the remodeling of the extracellular matrix (ECM), and a parabolic PDE governing the evolution of the matrix degrading enzyme (MDE) concentration. In addition to random diffusion, tumor cells are biased towards higher ECM density, which is referred to as Haptotaxis. Under a restrictive assumption on the coefficients, the global existence and uniqueness of classical solutions to the model in two dimensions, along with the boundedness of solutions in two and three dimensions, is proved by establishing some delicate a priori estimates.
Charles A Whittaker - One of the best experts on this subject based on the ideXlab platform.
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tumor cell driven extracellular matrix remodeling drives Haptotaxis during metastatic progression
Cancer Discovery, 2016Co-Authors: Madeleine J Oudin, Sreeja B. Asokan, Tatsiana Kosciuk, Oliver Jonas, Liliane C Broye, Bruna C Guido, Jeffrey Wyckoff, Daisy N Riquelme, John M Lamar, Charles A WhittakerAbstract:Fibronectin (FN) is a major component of the tumor microenvironment, but its role in promoting metastasis is incompletely understood. Here, we show that FN gradients elicit directional movement of breast cancer cells, in vitro and in vivo . Haptotaxis on FN gradients requires direct interaction between α5β1 integrin and MENA, an actin regulator, and involves increases in focal complex signaling and tumor cell–mediated extracellular matrix (ECM) remodeling. Compared with MENA, higher levels of the prometastatic MENAINV isoform associate with α5, which enables 3-D Haptotaxis of tumor cells toward the high FN concentrations typically present in perivascular space and in the periphery of breast tumor tissue. MENAINV and FN levels were correlated in two breast cancer cohorts, and high levels of MENAINV were significantly associated with increased tumor recurrence as well as decreased patient survival. Our results identify a novel tumor cell–intrinsic mechanism that promotes metastasis through ECM remodeling and ECM-guided directional migration. Significance: Here, we provide new insight into how tumor cell:ECM interactions generate signals and structures that promote directed tumor cell migration, a critical component of metastasis. Our results identify a tumor cell–intrinsic mechanism driven by the actin regulatory protein MENA that promotes ECM remodeling and Haptotaxis along FN gradients. Cancer Discov; 6(5); 516–31. ©2016 AACR. See related commentary by Santiago-Medina and Yang, [p. 474][1] . This article is highlighted in the In This Issue feature, [p. 461][2] [1]: /lookup/volpage/6/474?iss=5 [2]: /lookup/volpage/6/461?iss=5
Sreeja B. Asokan - One of the best experts on this subject based on the ideXlab platform.
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Lamellipodia are crucial for haptotactic sensing and response.
Journal of Cell Science, 2016Co-Authors: Samantha J. King, Sreeja B. Asokan, Elizabeth M. Haynes, Seth P. Zimmerman, Jeremy D. Rotty, James G. Alb, Alicia C. Tagliatela, Devon R. Blake, Irina P. Lebedeva, Daniel J. MarstonAbstract:ABSTRACT Haptotaxis is the process by which cells respond to gradients of substrate-bound cues, such as extracellular matrix proteins (ECM); however, the cellular mechanism of this response remains poorly understood and has mainly been studied by comparing cell behavior on uniform ECMs with different concentrations of components. To study Haptotaxis in response to gradients, we utilized microfluidic chambers to generate gradients of the ECM protein fibronectin, and imaged the cell migration response. Lamellipodia are fan-shaped protrusions that are common in migrating cells. Here, we define a new function for lamellipodia and the cellular mechanism required for Haptotaxis – differential actin and lamellipodial protrusion dynamics lead to biased cell migration. Modest differences in lamellipodial dynamics occurring over time periods of seconds to minutes are summed over hours to produce differential whole cell movement towards higher concentrations of fibronectin. We identify a specific subset of lamellipodia regulators as being crucial for Haptotaxis. Numerous studies have linked components of this pathway to cancer metastasis and, consistent with this, we find that expression of the oncogenic Rac1 P29S mutation abrogates Haptotaxis. Finally, we show that Haptotaxis also operates through this pathway in 3D environments.
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tumor cell driven extracellular matrix remodeling drives Haptotaxis during metastatic progression
Cancer Discovery, 2016Co-Authors: Madeleine J Oudin, Sreeja B. Asokan, Tatsiana Kosciuk, Oliver Jonas, Liliane C Broye, Bruna C Guido, Jeffrey Wyckoff, Daisy N Riquelme, John M Lamar, Charles A WhittakerAbstract:Fibronectin (FN) is a major component of the tumor microenvironment, but its role in promoting metastasis is incompletely understood. Here, we show that FN gradients elicit directional movement of breast cancer cells, in vitro and in vivo . Haptotaxis on FN gradients requires direct interaction between α5β1 integrin and MENA, an actin regulator, and involves increases in focal complex signaling and tumor cell–mediated extracellular matrix (ECM) remodeling. Compared with MENA, higher levels of the prometastatic MENAINV isoform associate with α5, which enables 3-D Haptotaxis of tumor cells toward the high FN concentrations typically present in perivascular space and in the periphery of breast tumor tissue. MENAINV and FN levels were correlated in two breast cancer cohorts, and high levels of MENAINV were significantly associated with increased tumor recurrence as well as decreased patient survival. Our results identify a novel tumor cell–intrinsic mechanism that promotes metastasis through ECM remodeling and ECM-guided directional migration. Significance: Here, we provide new insight into how tumor cell:ECM interactions generate signals and structures that promote directed tumor cell migration, a critical component of metastasis. Our results identify a tumor cell–intrinsic mechanism driven by the actin regulatory protein MENA that promotes ECM remodeling and Haptotaxis along FN gradients. Cancer Discov; 6(5); 516–31. ©2016 AACR. See related commentary by Santiago-Medina and Yang, [p. 474][1] . This article is highlighted in the In This Issue feature, [p. 461][2] [1]: /lookup/volpage/6/474?iss=5 [2]: /lookup/volpage/6/461?iss=5
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abstract c14 loss of Haptotaxis facilitates invasion in lkb1 deficient melanoma
Cancer Research, 2013Co-Authors: Keefe T Chan, Sreeja B. Asokan, Matthew E Berginski, Wenjin Liu, Shelly D Cochran, Norman E Sharpless, James E BearAbstract:Germline mutations in the serine/threonine kinase STK11/LKB1 are associated with Peutz-Jehgers Syndrome, which is characterized by hyperpigmentation of the oral mucosa. Inactivating somatic mutations occur in approximately 10-20% of melanomas; however, how the loss of LKB1 facilitates melanoma invasion remains poorly understood. Using cell lines derived from simultaneous activation of KRas and inactivation of LKB1 in melanocytes, we have investigated melanoma migration upon reconstitution with LKB1. Reexpression of LKB1 diminishes migration during wound healing, spheroid outgrowth into 3D collagen, and overall single cell speed in random motility assays. Furthermore, the formation of invadopodia is independent of LKB1 status in both human and mouse melanomas. Interestingly, using microfluidic devices we have found that loss of LKB1 abrogates the ability of cells to respond to gradients of extracellular matrix (Haptotaxis) but does not impair their ability to chemotax to EGF. We have also recently developed a model of orthotopic implantation of multicellular tumor spheroids into the dermis of the mouse ear skin and have validated this approach by recapitulating the finding that LKB1 limits tumorigenesis. We are using this model to image local invasion in vivo by multiphoton microscopy and are currently examining the intriguing hypothesis that loss of extracellular matrix sensing is one aspect that contributes to metastatic migration. Citation Format: Keefe T. Chan, Sreeja B. Asokan, Tao Bo, Matthew E. Berginski, Wenjin Liu, Shelly D. Cochran, Norman E. Sharpless, James E. Bear. Loss of Haptotaxis facilitates invasion in LKB1-deficient melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C14.
Tatsiana Kosciuk - One of the best experts on this subject based on the ideXlab platform.
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tumor cell driven extracellular matrix remodeling drives Haptotaxis during metastatic progression
Cancer Discovery, 2016Co-Authors: Madeleine J Oudin, Sreeja B. Asokan, Tatsiana Kosciuk, Oliver Jonas, Liliane C Broye, Bruna C Guido, Jeffrey Wyckoff, Daisy N Riquelme, John M Lamar, Charles A WhittakerAbstract:Fibronectin (FN) is a major component of the tumor microenvironment, but its role in promoting metastasis is incompletely understood. Here, we show that FN gradients elicit directional movement of breast cancer cells, in vitro and in vivo . Haptotaxis on FN gradients requires direct interaction between α5β1 integrin and MENA, an actin regulator, and involves increases in focal complex signaling and tumor cell–mediated extracellular matrix (ECM) remodeling. Compared with MENA, higher levels of the prometastatic MENAINV isoform associate with α5, which enables 3-D Haptotaxis of tumor cells toward the high FN concentrations typically present in perivascular space and in the periphery of breast tumor tissue. MENAINV and FN levels were correlated in two breast cancer cohorts, and high levels of MENAINV were significantly associated with increased tumor recurrence as well as decreased patient survival. Our results identify a novel tumor cell–intrinsic mechanism that promotes metastasis through ECM remodeling and ECM-guided directional migration. Significance: Here, we provide new insight into how tumor cell:ECM interactions generate signals and structures that promote directed tumor cell migration, a critical component of metastasis. Our results identify a tumor cell–intrinsic mechanism driven by the actin regulatory protein MENA that promotes ECM remodeling and Haptotaxis along FN gradients. Cancer Discov; 6(5); 516–31. ©2016 AACR. See related commentary by Santiago-Medina and Yang, [p. 474][1] . This article is highlighted in the In This Issue feature, [p. 461][2] [1]: /lookup/volpage/6/474?iss=5 [2]: /lookup/volpage/6/461?iss=5
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abstract 5057 mena at the nexus of chemotaxis and Haptotaxis during tumor progression
Cancer Research, 2015Co-Authors: Madeleine J Oudin, Miles A Miller, Tatsiana Kosciuk, Joelle Klazen, Alisha Lussiez, Douglas A Lauffenburger, James E Bear, Frank B GertlerAbstract:Directed-cell migration is key step in the metastatic cascade, and multiple cues can promote local invasion. The most well studied mode of cell motility for metastasizing tumor cells is chemotaxis, the directional movement of cells attracted to a source of soluble cues. In contrast, Haptotaxis, migration of cells on gradients of substrate-bound factors, remains poorly understood. Mena, an actin regulatory protein, plays an important role in cell motility and is upregulated in various cancers, driving migration in response to chemotactic and haptotactic cues. We have recently shown expression of the pro-metastatic isoform of Mena, MenaINV, increases sensitivity to growth factors (EGF, HGF and IGF) via dysregulation of the phosphatase PTP1B, as well as high concentrations of fibronectin (FN) via its interaction with the integrin α5β1. We hypothesized that MenaINV may also promote crosstalk between these two pathways to drive metastasis. First, we show that MenaINV-driven Haptotaxis on FN gradients and FN-driven invasion requires crosstalk between α5β1 and EGFR. Indeed, we show evidence that MenaINV expression is associated high phosphorylation of EGFR in high FN environments in vitro and in human breast cancer databases. Second, we find that MenaINV promotes synergy between EGF and FN in vitro and in vivo, leading to hyper-invasive phenotypes that drive more invasion than which each cue alone. Finally, we show that MenaINV-driven Haptotaxis, ECM reorganization and 3D invasion requires RCP-dependent recycling of α5β1 and EGFR. Together, our data demonstrate that MenaINV is a shared component of the machinery that mediates both haptotactic responses to FN and chemotactic responses to EGF, two pathways that promote tumor progression. Citation Format: Madeleine J. Oudin, Miles A. Miller, Tatsiana Kosciuk, Joelle Klazen, Alisha Lussiez, Douglas Lauffenburger, James E. Bear, Frank B. Gertler. Mena at the nexus of chemotaxis and Haptotaxis during tumor progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5057.
