EP4 receptor promotes invadopodia and invasion in human breast cancer

Tönisen, Felix; Perrin, Louisiane; Bayarmagnai, Battuya; Dries, Koen van den; Cambi, Alessandra; Gligorijevic, Bojana

doi:10.1016/j.ejcb.2016.12.005

Cited by 19 publications

(19 citation statements)

References 42 publications

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“…Our model and results of blocking interactions between ECM and b1-integrin suggest that the balance between migration and invadopodia states can be altered via ECM-b1-integrin binding levels. Previous reports of dose response to soluble factors such as epidermal growth factor demonstrated similar biphasic trends of invadopodia numbers and/or chemotactic migration to increasing epidermal growth factor concentrations (47)(48)(49). Taken together, these data suggest that conditions in the extracellular environment cannot be directly taken as having a positive or negative effect on motility or invadopodia functions.…”

Section: Discussionsupporting

confidence: 67%

ECM Cross-Linking Regulates Invadopodia Dynamics

Pourfarhangi

Bergman

Gligorijevic

2018

Biophysical Journal

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Invadopodia are membrane protrusions dynamically assembled by invasive cancer cells in contact with the extracellular matrix (ECM). Invadopodia are enriched by the structural proteins actin and cortactin as well as metalloproteases such as MT1-MMP, whose function is to degrade the surrounding ECM. During metastasis, invadopodia are necessary for cancer cell intravasation and extravasation. Although signaling pathways involved in the assembly and function of invadopodia are well studied, few studies address invadopodia dynamics and how the cell-ECM interactions contribute to cell invasion. Using iterative analysis based on time-lapse microscopy and mathematical modeling of invasive cancer cells, we found that cells oscillate between invadopodia presence and cell stasis-termed the "invadopodia state"-and invadopodia absence during cell translocation-termed the "migration state." Our data suggest that β1-integrin-ECM binding and ECM cross-linking control the duration of each of the two states. By changing the concentration of cross-linkers in two-dimensional and three-dimensional cultures, we generate an ECM in which 0-0.92 of total lysine residues are cross-linked. Using an ECM with a range of cross-linking degrees, we demonstrate that the dynamics of invadopodia-related functions have a biphasic relationship to ECM cross-linking. At intermediate levels of ECM cross-linking (0.39), cells exhibit rapid invadopodia protrusion-retraction cycles and rapid calcium spikes, which lead to more frequent MT1-MMP delivery, causing maximal invadopodia-mediated ECM degradation. In contrast, both extremely high or low levels of cross-linking lead to slower invadopodia-related dynamics and lower ECM degradation. Additionally, β1-integrin inhibition modifies the dynamics of invadopodia-related functions as well as the length of time cells spend in either of the states. Collectively, these data suggest that β1-integrin-ECM binding nonlinearly translates small physical differences in the extracellular environment to differences in the dynamics of cancer cell behaviors. Understanding the conditions under which invadopodia can be reduced by subtle environment-targeting treatments may lead to combination therapies for preventing metastatic spread.

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Section: Discussionsupporting

confidence: 67%

ECM Cross-Linking Regulates Invadopodia Dynamics

Pourfarhangi

Bergman

Gligorijevic

2018

Biophysical Journal

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“…Our model and results of blocking ECM-integrin β1 interactions suggest that the balance between migration and Invadopodia states can be altered via ECM-β1-integrin binding levels. Previous reports of dose-response to soluble factors such as EGF, demonstrated similar, biphasic trends of invadopodia numbers and/or chemotactic migration to increasing EGF concentrations (41)(42)(43). Taken together, these data suggest that conditions in the extracellular environment cannot be directly taken as having a positive or negative effect on motility or invadopodial functions.…”

Section: Discussionsupporting

confidence: 69%

ECM cross-linking regulates invadopodia dynamics

Pourfarhangi

Bergman

Gligorijevic

2017

Preprint

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Invadopodia are membrane protrusions dynamically assembled by invasive cancer cells in contact with extracellular matrix (ECM). Invadopodia are enriched for the structural proteins actin and cortactin, as well as metalloproteases such as MT1-MMP, whose function is to degrade the surrounding ECM. During metastasis, invadopodia are necessary for cancer cell intravasation and extravasation. While signaling pathways involved in the assembly and function of invadopodia are well studied, few studies address invadopodia dynamics and how the cell-ECM interactions contribute to cell invasion. Using iterative analysis based on time-lapse microscopy and mathematical modeling of invasive cancer cells, we found that cells oscillate between invadopodia presence and cell stasis, termed Invadopodia state and invadopodia absence during cell translocation, termed Migration state. Our data suggests that β1-integrin-ECM binding and ECM cross-linking control the duration of each of the two states. By changing the concentration of cross-linkers in 2D and 3D cultures, we generate ECM where 0-0.92 of total lysine residues are cross-linked. Using ECM with a range of cross-linking degrees we demonstrate that the dynamics of invadopodia-related functions have a biphasic relationship to ECM cross-linking. At intermediate levels of ECM cross-linking (0.39), cells exhibit rapid invadopodia protrusionretraction cycles and rapid calcium spikes, which lead to more frequent MT1-MMP delivery, causing maximal invadopodia-mediated ECM degradation. In contrast, both extremely high or low levels of cross-linking lead to slower invadopodia-related dynamics and lower ECM degradation. Additionally, β1-integrin inhibition modifies dynamics of invadopodia-related functions, as well as the length of time cells spend in either of the states. Collectively, these data suggest that β1-integrin-ECM binding non-linearly translates small physical differences in extracellular environment to differences in the dynamics of cancer cell behaviors. Understanding conditions under which invadopodia can be reduced by subtle environment-targeting treatments may lead to combination therapies for preventing metastatic spread.

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“…Invasion through the genesis of invadopodia illustrate a dependence on prostaglandin signaling [246]. Intravital fluorescence microscopy has also revealed dynamic platelet-melanoma cell interactions in mice [247].…”

Section: Hematogenous Spread Extravasation and Secondary Site Metastmentioning

confidence: 99%

Platelet “first responders” in wound response, cancer, and metastasis

Menter

Kopetz

Hawk

et al. 2017

Cancer Metastasis Rev

146

115

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Platelets serve as “First Responders” during normal wounding and homeostasis. Arising from bone marrow stem cell lineage megakaryocytes, anucleate platelets can influence inflammation and immune regulation. Biophysically, platelets are optimized due to size and discoid morphology to distribute near vessel walls, monitor vascular integrity and initiate quick responses to vascular lesions. Adhesion receptors linked to a highly reactive filopodia-generating cytoskeleton maximizes their vascular surface contact allowing rapid response capabilities. Functionally, platelets normally initiate rapid clotting, vasoconstriction, inflammation and wound biology that leads to sterilization, tissue repair and resolution. Platelets also are among the first to sense, phagocytize, decorate, or react to pathogens in the circulation. These platelet first responder properties are commandeered during chronic inflammation, cancer progression and metastasis. Leaky or inflammatory reaction blood vessel genesis during carcinogenesis provides opportunities for platelet invasion into tumors. Cancer is thought of as a non-healing or chronic wound that can be actively aided by platelet mitogenic properties to stimulate tumor growth. This growth ultimately outstrips circulatory support leads to angiogenesis and intravasation of tumor cells into the blood stream. Circulating tumor cells reengage additional platelets, which facilitates tumor cell adhesion, arrest and extravasation and metastasis. This process, along with the hypercoagulable states associated with malignancy is amplified by IL6 production in tumors that stimulate liver thrombopoietin production and elevates circulating platelet numbers by thrombopoiesis in the bone marrow. These complex interactions and the “First Responder” role of platelets during diverse physiologic stresses provides a useful therapeutic target that deserves further exploration.

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EP4 receptor promotes invadopodia and invasion in human breast cancer

Cited by 19 publications

References 42 publications

ECM Cross-Linking Regulates Invadopodia Dynamics

ECM Cross-Linking Regulates Invadopodia Dynamics

ECM cross-linking regulates invadopodia dynamics

Platelet “first responders” in wound response, cancer, and metastasis

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