ECM Cross-Linking Regulates Invadopodia Dynamics

Pourfarhangi, Kamyar Esmaeili; Bergman, Aviv; Gligorijevic, Bojana

doi:10.1016/j.bpj.2018.01.027

Cited by 41 publications

(49 citation statements)

References 59 publications

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“…39 Furthermore, similar to cell migration, invasion and ECM degradation can be modulated by external factors, such as soluble cues and ECM parameters. [40][41][42][43] In addition, intrinsic cellular activities, such as cell cycle, can also affect the ECM degradation. Recent study has shown that the cytoplasmic pool of cyclin-dependent kinase inhibitor p27 is involved in regulation of ECM degradation.…”

Section: Discussionmentioning

confidence: 99%

Directed, but not random, breast cancer cell migration is faster in the G1 phase of the cell cycle in 2D and 3D environments

et al. 2018

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Cancer cell migration is essential for the early steps of metastasis, during which cancer cells move through the primary tumor and reach the blood vessels. In vivo, cancer cells are exposed to directional guidance cues, either soluble, such as gradients of growth factors, or insoluble, such as collagen fiber alignment. Depending on the number and strength of such cues, cells will migrate in a random or directed manner. Interestingly, similar cues also stimulate cell proliferation. In this regard, it is not clear whether cell cycle progression affects migration of cancer cells and whether this effect is different in random versus directed migration. In this study, we tested the effect of cell cycle progression on random and directed migration, both in 2D and 3D environments, in the breast carcinoma cell line, FUCCI-MDA-MB-231, using computational image analysis by LEVER. Directed migration in 2D was modeled as chemotaxis along a gradient of soluble EGF inside 10 µm-wide microchannels. In 3D, directed migration was modeled as contact guidance (alignotaxis) along aligned collagen fibers. Time-lapse recordings of cells in 2D and 3D revealed that directed, but not random migration, is cell cycle-dependent. In both 2D and 3D directed migration, cells in the G1 phase of the cell cycle outperformed cells in the G2 phase in terms of migration persistence and instantaneous velocity. These data suggest that in the presence of guidance cues in vivo, breast carcinoma cells in the G1 phase of the cell cycle may be more efficient in reaching vasculature.not peer-reviewed)

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Section: Discussionmentioning

confidence: 99%

Directed, but not random, breast cancer cell migration is faster in the G1 phase of the cell cycle in 2D and 3D environments

et al. 2018

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“…Use of this approach, titled intravital systems microscopy was instrumental in demonstrating a direct link between the local microenvironment parameters in tumors, the assembly of invadopodia in tumor cells, and the ability of those tumor cells to intravasate and metastasize in vivo . This work also indicated that tumor cell behavior is a result of complex interactions among cues present in the tumor microenvironment and that machine learning algorithms have the ability to grasp this complexity …”

Section: Towards Multiparametric Iv‐mpm Of Cancer: New Imaging and Immentioning

confidence: 99%

“…41,42 This work also indicated that tumor cell behavior is a result of complex interactions among cues present in the tumor microenvironment and that machine learning algorithms have the ability to grasp this complexity. 18,43 In neuroscience and developmental biology, the field of computer science is contributing new image processing and analysis workflows, advancing large-scale brain mapping [44][45][46] and analysis of tissue morphodynamics. [47][48][49] Implementing similar unbiased strategies for IV-MPM studies of cancer will allow us to accelerate the pace of discoveries.…”

Section: (Semi)automated Image Processing and Machine Learning Clasmentioning

confidence: 99%

Frontiers in intravital multiphoton microscopy of cancer

2019

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Background Cancer is a highly complex disease, which involves the cooperation of tumor cells with multiple types of host cells and the extracellular matrix. Cancer studies that rely solely on static measurements of individual cell types are insufficient to dissect this complexity. In the last two decades, intravital microscopy has established itself as a powerful technique that can significantly improve our understanding of cancer by revealing the dynamic interactions governing cancer initiation, progression, and treatment effects in living animals. This review focuses on intravital multiphoton microscopy (IV‐MPM) applications in mouse models of cancer. Recent findings IV‐MPM studies have already enabled a deeper understanding of the complex events occurring in cancer at the molecular, cellular, and tissue levels. Multiple cell types present in different tissues influence cancer cell behavior via activation of distinct signaling pathways. As a result, the boundaries in the field of IV‐MPM are continuously being pushed to provide an integrated comprehension of cancer. We propose that optics, informatics, and cancer (cell) biology are coevolving as a new field. We have identified four emerging themes in this new field. First, new microscopy systems and image processing algorithms are enabling the simultaneous identification of multiple interactions between the tumor cells and the components of the tumor microenvironment. Second, techniques from molecular biology are being exploited to visualize subcellular structures and protein activities within individual cells of interest and relate those to phenotypic decisions, opening the door for “in vivo cell biology”. Third, combining IV‐MPM with additional imaging modalities or omics studies holds promise for linking the cell phenotype to its genotype, metabolic state, or tissue location. Finally, the clinical use of IV‐MPM for analyzing efficacy of anticancer treatments is steadily growing, suggesting a future role of IV‐MPM for personalized medicine. Conclusion IV‐MPM has revolutionized visualization of tumor‐microenvironment interactions in real time. Moving forward, incorporation of novel optics, automated image processing, and omics technologies in the study of cancer biology, will not only advance our understanding of the underlying complexities but will also leverage the unique aspects of IV‐MPM for clinical use.

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“…The size and the number of the degradation spots are known to reflect invadopodia lifetime 4 . Invadopodia exert mechanical forces onto the ECM via protrusion-retraction oscillations 10 . These oscillations, along with the delivery of MT1-MMP, lead to the degradation of the surrounding ECM, i.e.…”

Section: Cyclin-dependent Kinase Inhibitor P27 Kip1 Localizes To Invamentioning

confidence: 99%

“…We previously demonstrated that the invasive cells oscillate between two distinct states, termed the Invadopodia state and the Migration state (Esmaeili Pourfarhangi, Bergman, and Gligorijevic 2018a). The Invadopodia state is characterized by cell stasis and the presence of invadopodia, while the Migration state is defined by cell translocation in the absence of invadopodia.…”

Section: Introductionmentioning

confidence: 99%

Invadopodia degrade ECM in the G1 phase of the cell cycle

Bayarmagnai

Perrin

et al. 2018

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Invadopodia are cancer cell protrusions rich in structural proteins (e.g. Tks5, cortactin) and proteases (e.g. MT1-MMP) and are responsible for degradation of the extracellular matrix (ECM). Tumor cell invasion and metastasis require cancer cells to be both proliferative and invasive, i.e. migrate through the tissue and assemble invadopodia.While several studies addressed how cell motility parameters change throughout the cell cycle, the relationship between invadopodia and cell cycle progression has not been elucidated. In this study, using invadopodia-and cell cycle-fluorescent markers, we show in 2D-and 3D-cell cultures, as well as in vivo, that breast carcinoma cells assemble invadopodia and invade into the surrounding ECM preferentially during the G1 phase of the cell cycle. Cells synchronized in the G0/G1 phase of the cell cycle degrade at significantly higher levels during the first 20 hours post-synchronization release. Consistent with this, mRNA and protein levels of the invadopodia core components, cortactin and MT1-MMP, peak at 14 hours post-release. We demonstrate that the cell cycle progression is faster in cells with abolished invadopodia (Tks5 knockdown, Tks5-KD), evidenced by earlier induction of cyclins A and B. Closer look at the regulators of G1 revealed that the overexpression of p27 kip1 , but not p21 cip1 , causes faster turnover of invadopodia and increased ECM degradation. Furthermore, we show that both endogenous and over-expressed p27 kip1 localize to the sites of invadopodia assembly. Taken together, these findings suggest that the invadopodia function is tightly linked to cell cycle progression and is controlled by cell cycle regulators. Our results caution that the coordination of invasion and cell cycle must be considered when designing effective chemotherapies.

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ECM Cross-Linking Regulates Invadopodia Dynamics

Cited by 41 publications

References 59 publications

Directed, but not random, breast cancer cell migration is faster in the G1 phase of the cell cycle in 2D and 3D environments

Directed, but not random, breast cancer cell migration is faster in the G1 phase of the cell cycle in 2D and 3D environments

Frontiers in intravital multiphoton microscopy of cancer

Invadopodia degrade ECM in the G1 phase of the cell cycle

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