Quantitative elucidation of a distinct spatial gradient-sensing mechanism in fibroblasts

Schneider, Ian C.; Haugh, Jason M.

doi:10.1083/jcb.200509028

Cited by 100 publications

(108 citation statements)

References 50 publications

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“…Our computational model suggested that slow interstitial flow can cause pericellular CXCL12 gradients of at least 1% to form around a circular cell. Such gradients are sufficient to elicit directional migration in other cell types including neutrophils (37), fibroblasts (38), and dendritic cells (39). We, in fact, see both directional cell polarization and migration in response to flow through our studies possibly indicating a role for autologous chemotaxis complementary to enhanced chemokinesis.…”

Section: Discussionmentioning

confidence: 49%

Interstitial Flow in a 3D Microenvironment Increases Glioma Invasion by a CXCR4-Dependent Mechanism

2013

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Brain tumor invasion leads to recurrence and resistance to treatment. Glioma cells invade in distinct patterns, possibly determined by microenvironmental cues including chemokines, structural heterogeneity, and fluid flow. We hypothesized that flow originating from pressure differentials between the brain and tumor is active in glioma invasion. Using in vitro models, we show that interstitial flow promotes cell invasion in multiple glioma cell lines. Flow effects were CXCR4-dependent, because they were abrogated by CXCR4 inhibition. Furthermore, CXCR4 was activated in response to flow, which could be responsible for enhanced cell motility. Flow was seen to enhance cell polarization in the flow direction, and this flow-induced polarization could be blocked by CXCR4 inhibition or CXCL12 oversaturation in the matrix. Furthermore, using live imaging techniques in a three-dimensional flow chamber, there were more cells migrating and more cells migrating in the direction of flow. This study shows that interstitial flow is an active regulator of glioma invasion. The new mechanisms of glioma invasion that we identify here-namely, interstitial flow-enhanced motility, activation of CXCR4, and CXCL12-driven autologous chemotaxis-are significant in therapy to prevent or treat brain cancer invasion. Current treatment strategies can lead to edema and altered flow in the brain, and one popular experimental treatment in clinical trials, convection enhanced delivery, involves enhancement of flow in and around the tumor. A better understanding of how interstitial flow at the tumor margin can alter chemokine distributions, cell motility, and directed invasion offers a better understanding of treatment failure. Cancer Res; 73(5); 1536-46. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 49%

Interstitial Flow in a 3D Microenvironment Increases Glioma Invasion by a CXCR4-Dependent Mechanism

2013

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“…Several Rac GEFs are activated by phosphatidylinositol-(3-5)-triphosphate, including Vav, Tiam1, PIX, and p-REX (46). Rac activity may be sustained through feedback loops, as Rac can interact with the p85 regulatory subunit of class 1A PI3Ks in leukocytes, although possibly not in fibroblasts (26,47). Although activation of Akt downstream of PI3K is implicated in cell migration via Rac/Pak pathway, the mechanism of Akt activation is poorly understood (48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide 3-Kinase δ Regulates Migration and Invasion of Synoviocytes in Rheumatoid Arthritis

Bartók

Hammaker

Firestein

2014

The Journal of Immunology

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Cartilage destruction mediated by invasive fibroblast-like synoviocytes (FLS) plays a central role in pathogenesis of rheumatoid arthritis (RA). Increased cell migration and degradation of extracellular matrix are fundamental to these processes. The class I PI3Ks control cell survival, proliferation, and migration, which might be involved in cartilage damage in RA. PI3Kδ isoform was recently identified as a key regulator of FLS growth and survival, suggesting that it could contribute to synoviocyte aggressive behavior. Therefore, we assessed the role of PI3Kδ in RA synoviocyte migration and invasion. We observed that PI3Kδ inhibition or small interfering RNA knockdown decreased platelet-derived growth factor (PDGF)–mediated migration and invasion of FLS. We then showed that PI3Kδ regulates the organization of actin cytoskeleton and lamellipodium formation during PDGF stimulation. To gain insight into molecular mechanisms, we examined the effect of PI3Kδ inhibition on Rac1/PAK, FAK, and JNK activation. Our studies suggest that Rac1/PAK is key target of PDGF-mediated PI3Kδ signaling, whereas FAK and JNK are not involved. Thus, PI3Kδ contributes to multiple aspects of the pathogenic FLS behavior in RA. These observations, together with previous findings that PI3Kδ regulates FLS growth and survival, suggest that PI3Kδ inhibition could be chondroprotective in RA by modulating synoviocyte growth, migration, and invasion.

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“…In fibroblasts, chemotaxis to PDGF is also characterised by polarised localisation of PtdIns(3,4,5)P 3 . However, modelling predicts that localised PtdIns(3,4,5)P 3 accumulation primarily reflects receptor occupancy and is not regulated by feedback amplification or inhibition proposed for ameboid cells (Schneider and Haugh, 2005). Indeed, migration of fibroblasts is slower than that of amoeboid cells and although driven by membrane protrusion, it also involves substantial contribution of differential adhesion (Lauffenburger and Horwitz, 1996), suggesting distinct requirements for gradient sensing.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, migration of fibroblasts is slower than that of amoeboid cells and although driven by membrane protrusion, it also involves substantial contribution of differential adhesion (Lauffenburger and Horwitz, 1996), suggesting distinct requirements for gradient sensing. Furthermore, it has been shown that robust PDGF sensing requires steeper gradients and a much narrower range of absolute chemoattractant concentration (Schneider and Haugh, 2005).…”

Section: Introductionmentioning

confidence: 99%

Activity of PLCε contributes to chemotaxis of fibroblasts towards PDGF

Martins

Warren

Kimberley

et al. 2012

Journal of Cell Science

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SummaryCell chemotaxis, such as migration of fibroblasts towards growth factors during development and wound healing, requires precise spatial coordination of signalling events. Phosphoinositides and signalling enzymes involved in their generation and hydrolysis have been implicated in regulation of chemotaxis; however, the role and importance of specific components remain poorly understood. Here, we demonstrate that phospholipase C epsilon (PLCe) contributes to fibroblast chemotaxis towards platelet-derived growth factor (PDGF-BB). Using PLCe1 null fibroblasts we show that cells deficient in PLCe have greatly reduced directionality towards PDGF-BB without detrimental effect on their basal ability to migrate. Furthermore, we show that in intact fibroblasts, signalling events, such as activation of Rac, are spatially compromised by the absence of PLCe that affects the ability of cells to enlarge their protrusions in the direction of the chemoattractant. By further application of live cell imaging and the use of FRET-based biosensors, we show that generation of Ins(1,4,5)P 3 and recruitment of PLCe are most pronounced in protrusions responding to the PDGF-BB gradient. Furthermore, the phospholipase C activity of PLCe is critical for its role in chemotaxis, consistent with the importance of Ins(1,4,5)P 3 generation and sustained calcium responses in this process. As PLCe has extensive signalling connectivity, using transgenic fibroblasts we ruled out its activation by direct binding to Ras or Rap GTPases, and suggest instead new unexpected links for PLCe in the context of chemotaxis.

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Quantitative elucidation of a distinct spatial gradient-sensing mechanism in fibroblasts

Cited by 100 publications

References 50 publications

Interstitial Flow in a 3D Microenvironment Increases Glioma Invasion by a CXCR4-Dependent Mechanism

Interstitial Flow in a 3D Microenvironment Increases Glioma Invasion by a CXCR4-Dependent Mechanism

Phosphoinositide 3-Kinase δ Regulates Migration and Invasion of Synoviocytes in Rheumatoid Arthritis

Activity of PLCε contributes to chemotaxis of fibroblasts towards PDGF

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