Dataset Information

?3 integrin expression is required for invadopodia-mediated ECM degradation in lung carcinoma cells.

ABSTRACT: Cancer related deaths are primarily due to tumor metastasis. To facilitate their dissemination to distant sites, cancer cells develop invadopodia, actin-rich protrusions capable of degrading the surrounding extracellular matrix (ECM). We aimed to determine whether ?3 integrin participates in invadopodia formed by lung carcinoma cells, based on our previous findings of specific TGF-? induction of ?3 integrin dependent metastasis in animal models of lung carcinoma. In this study, we demonstrate that lung carcinoma cells form invadopodia in response to TGF-? exposure. Invadopodia formation and degradation activity is dependent on ?3 integrin expression since ?3 integrin deficient cells are not able to degrade gelatin-coated surfaces. Even more, transient over-expression of SRC did not restore invadopodia formation in ?3 integrin deficient cells. Finally, we observed that blockade of PLC-dependent signaling leads to more intense labeling for ?3 integrin in invadopodia. Our results suggest that ?3 integrin function, and location, in lung cancer cells are essential for invadopodia formation, and this integrin regulates the activation of different signal pathways necessary for the invasive structure. ?3 integrin has been associated with poor prognosis and increased metastasis in several carcinoma types, including lung cancer. Our findings provide new evidence to support the use of targeted therapies against this integrin to combat the onset of metastases.

SUBMITTER: Pelaez R

PROVIDER: S-EPMC5540285 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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β3 integrin expression is required for invadopodia-mediated ECM degradation in lung carcinoma cells.

Peláez Rafael R Morales Xabier X Salvo Elizabeth E Garasa Saray S Ortiz de Solórzano Carlos C Martínez Alfredo A Larrayoz Ignacio M IM Rouzaut Ana A

PloS one 20170802 8

Cancer related deaths are primarily due to tumor metastasis. To facilitate their dissemination to distant sites, cancer cells develop invadopodia, actin-rich protrusions capable of degrading the surrounding extracellular matrix (ECM). We aimed to determine whether β3 integrin participates in invadopodia formed by lung carcinoma cells, based on our previous findings of specific TGF-β induction of β3 integrin dependent metastasis in animal models of lung carcinoma. In this study, we demonstrate th ...[more]

PMID: 28767724

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Project description:Focal degradation of extracellular matrix (ECM) is the first step in the invasion of cancer cells. MT1-MMP is a potent membrane proteinase employed by aggressive cancer cells. In our previous study, we reported that MT1-MMP was preferentially located at membrane protrusions called invadopodia, where MT1-MMP underwent quick turnover. Our computer simulation and experiments showed that this quick turnover was essential for the degradation of ECM at invadopodia (Hoshino, D., et al., (2012) PLoS Comp. Biol., 8: e1002479). Here we report on characterization and analysis of the ECM-degrading activity of MT1-MMP, aiming at elucidating a possible reason for its repetitive insertion in the ECM degradation. First, in our computational model, we found a very narrow transient peak in the activity of MT1-MMP followed by steady state activity. This transient activity was due to the inhibition by TIMP-2, and the steady state activity of MT1-MMP decreased dramatically at higher TIMP-2 concentrations. Second, we evaluated the role of the narrow transient activity in the ECM degradation. When the transient activity was forcibly suppressed in computer simulations, the ECM degradation was heavily suppressed, indicating the essential role of this transient peak in the ECM degradation. Third, we compared continuous and pulsatile turnover of MT1-MMP in the ECM degradation at invadopodia. The pulsatile insertion showed basically consistent results with the continuous insertion in the ECM degradation, and the ECM degrading efficacy depended heavily on the transient activity of MT1-MMP in both models. Unexpectedly, however, low-frequency/high-concentration insertion of MT1-MMP was more effective in ECM degradation than high-frequency/low-concentration pulsatile insertion even if the time-averaged amount of inserted MT1-MMP was the same. The present analysis and characterization of ECM degradation by MT1-MMP together with our previous report indicate a dynamic nature of MT1-MMP at invadopodia and the importance of its transient peak in the degradation of the ECM.

Project description: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 ?1-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, ?1-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 ?1-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.

Dataset Information

?3 integrin expression is required for invadopodia-mediated ECM degradation in lung carcinoma cells.

Publications

β3 integrin expression is required for invadopodia-mediated ECM degradation in lung carcinoma cells.

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