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Experimental Cell Research Apr 2016Mechanical rigidity in the tumor microenvironment is associated with a high risk of tumor formation and aggressiveness. Adhesion-based signaling driven by a rigid... (Review)
Review
Mechanical rigidity in the tumor microenvironment is associated with a high risk of tumor formation and aggressiveness. Adhesion-based signaling driven by a rigid microenvironment is thought to facilitate invasion and migration of cancer cells away from primary tumors. Proteolytic degradation of extracellular matrix (ECM) is a key component of this process and is mediated by subcellular actin-rich structures known as invadopodia. Both ECM rigidity and cellular traction stresses promote invadopodia formation and activity, suggesting a role for these structures in mechanosensing. The presence and activity of mechanosensitive adhesive and signaling components at invadopodia further indicates the potential for these structures to utilize myosin-dependent forces to probe and remodel their ECM environments. Here, we provide a brief review of the role of adhesion-based mechanical signaling in controlling invadopodia and invasive cancer behavior.
Topics: Extracellular Matrix; Humans; Mechanotransduction, Cellular; Models, Biological; Podosomes; Tumor Microenvironment
PubMed: 26546985
DOI: 10.1016/j.yexcr.2015.10.038 -
Frontiers in Immunology 2018The immune system serves as a crucial line of defense from infection and cancer, while also contributing to tissue homeostasis. Communication between immune cells is... (Review)
Review
The immune system serves as a crucial line of defense from infection and cancer, while also contributing to tissue homeostasis. Communication between immune cells is mediated by small soluble factors called cytokines, and also by direct cellular interactions. Cell-cell interactions are particularly important for T cell activation. T cells direct the adaptive immune response and therefore need to distinguish between self and foreign antigens. Even though decades have passed since the discovery of T cells, exactly why and how they are able to recognize and discriminate between antigens is still not fully understood. Early imaging of T cells was very successful in capturing the early stages of conjugate formation of T cells with antigen-presenting cells upon recognition of peptide-loaded major histocompatibility complexes by the T cell receptor (TCR). These studies lead to the discovery of a "supramolecular activation cluster" now known as the immunological synapse, followed by the identification of microclusters of TCRs formed upon receptor triggering, that eventually coalesce at the center of the synapse. New developments in light microscopy have since allowed attention to turn to the very earliest stages of T cell activation, and to resting cells, at high resolution. This includes single-molecule localization microscopy, which has been applied to the question of whether TCRs are pre-clustered on resting T cells, and lattice light-sheet microscopy that has enabled imaging of whole cells interacting with antigen-presenting cells. The utilization of lattice light-sheet microscopy has yielded important insights into structures called microvilli, which are small membrane protrusions on T cells that seem likely to have a large impact on T cell recognition and activation. Here we consider how imaging has shaped our thinking about T cell activation. We summarize recent findings obtained by applying more advanced microscopy techniques and discuss some of the limitations of these methods.
Topics: Cell Communication; Humans; Immunological Synapses; Lymphocyte Activation; Microscopy, Confocal; Microscopy, Fluorescence; Microvilli; Podosomes; Receptors, Antigen, T-Cell; Single Molecule Imaging; T-Lymphocytes
PubMed: 30319617
DOI: 10.3389/fimmu.2018.02152 -
Handbook of Experimental Pharmacology 2017Cell migration is necessary for several developmental processes in multicellular organisms. Furthermore, many physiological processes such as wound healing and... (Review)
Review
Cell migration is necessary for several developmental processes in multicellular organisms. Furthermore, many physiological processes such as wound healing and immunological events in adult animals are dependent on cell migration. Consequently, defects in cell migration are linked to various diseases including immunological disorders as well as cancer progression and metastasis formation. Cell migration is driven by specific protrusive and contractile actin filament structures, but the types and relative contributions of these actin filament arrays vary depending on the cell type and the environment of the cell. In this chapter, we introduce the most important actin filament structures that contribute to mesenchymal and amoeboid cell migration modes and discuss the mechanisms by which the assembly and turnover of these structures are controlled by various actin-binding proteins.
Topics: Actin Cytoskeleton; Animals; Cell Movement; Humans; Myosins; Pseudopodia; Stress Fibers
PubMed: 27469496
DOI: 10.1007/164_2016_28 -
The FEBS Journal Oct 2022Invadosomes are protrusive and mechanosensitive actin devices critical for cell migration, invasion, and extracellular matrix remodeling. The dynamic, proteolytic, and... (Review)
Review
Invadosomes are protrusive and mechanosensitive actin devices critical for cell migration, invasion, and extracellular matrix remodeling. The dynamic, proteolytic, and protrusive natures of invadosomes have made these structures fascinating and attracted many scientists to develop new technologies for their analysis. With these exciting methodologies, many biochemical and biophysical properties of invadosomes have been well characterized and appreciated, and those discoveries elegantly explained the biological and pathological effects of invadosomes in human health and diseases. In this review, we focus on these commonly used or newly developed methods for invadosome analysis and effort to reason some discrepancies among those assays. Finally, we explore the opposite regulatory mechanisms among invadosomes and focal adhesions, another actin-rich adhesive structures, and speculate a potential rule for their switch.
Topics: Actins; Cell Movement; Extracellular Matrix; Humans; Podosomes; Proteolysis
PubMed: 34196119
DOI: 10.1111/febs.16098 -
Cancers May 2019Invadopodia are actin-rich protrusions developed by transformed cells in 2D/3D environments that are implicated in extracellular matrix (ECM) remodeling and degradation.... (Review)
Review
Invadopodia are actin-rich protrusions developed by transformed cells in 2D/3D environments that are implicated in extracellular matrix (ECM) remodeling and degradation. These structures have an undoubted association with cancer invasion and metastasis because invadopodium formation in vivo is a key step for intra/extravasation of tumor cells. Invadopodia are closely related to other actin-rich structures known as podosomes, which are typical structures of normal cells necessary for different physiological processes during development and organogenesis. Invadopodia and podosomes are included in the general term 'invadosomes,' as they both appear as actin puncta on plasma membranes next to extracellular matrix metalloproteinases, although organization, regulation, and function are slightly different. Integrins are transmembrane proteins implicated in cell-cell and cell-matrix interactions and other important processes such as molecular signaling, mechano-transduction, and cell functions, e.g., adhesion, migration, or invasion. It is noteworthy that integrin expression is altered in many tumors, and other pathologies such as cardiovascular or immune dysfunctions. Over the last few years, growing evidence has suggested a role of integrins in the formation of invadopodia. However, their implication in invadopodia formation and adhesion to the ECM is still not well known. This review focuses on the role of integrins in invadopodium formation and provides a general overview of the involvement of these proteins in the mechanisms of metastasis, taking into account classic research through to the latest and most advanced work in the field.
PubMed: 31052560
DOI: 10.3390/cancers11050615 -
Science Signaling Sep 2023Alternative splicing regulates gene expression and functional diversity and is often dysregulated in human cancers. Here, we discovered that the long noncoding RNA...
Alternative splicing regulates gene expression and functional diversity and is often dysregulated in human cancers. Here, we discovered that the long noncoding RNA (lncRNA) MIR99AHG regulated alternative splicing to alter the activity of a chromatin remodeler and promote metastatic behaviors in colorectal cancer (CRC). MIR99AHG was abundant in invasive CRC cells and metastatic tumors from patients and promoted motility and invasion in cultured CRC cells. MIR99AHG bound to and stabilized the RNA splicing factor PTBP1, and this complex increased cassette exon inclusion in the mRNA encoding the chromatin remodeling gene . Specifically, MIR99AHG altered the nature of PTBP1 binding to the splice sites on intron 12 of pre-mRNA, thereby triggering a splicing switch from skipping to including exon 13 to produce the long isoform, SMARCA1-L. SMARCA1, but not SMARCA1-L, suppressed invadopodia formation, cell migration, and invasion. Analysis of CRC samples revealed that the abundance of transcript positively correlated with that of mRNA and PTBP1 protein and with poor prognosis in patients with CRC. Furthermore, TGF-β1 secretion from cancer-associated fibroblasts increased expression in CRC cells. Our findings identify an lncRNA that is induced by cues from the tumor microenvironment and that interacts with PTBP1 to regulate alternative splicing, potentially providing a therapeutic target and predictive biomarker for metastatic CRC.
Topics: Humans; Alternative Splicing; Chromatin; Colorectal Neoplasms; Heterogeneous-Nuclear Ribonucleoproteins; Podosomes; Polypyrimidine Tract-Binding Protein; RNA Splicing; RNA, Long Noncoding; Tumor Microenvironment
PubMed: 37725664
DOI: 10.1126/scisignal.adh4210 -
Trends in Cell Biology Feb 2019Matrix proteolysis mediated by MT1-MMP facilitates the invasive migration of tumor cells in dense tissues, which otherwise get trapped in the matrix because of limited... (Review)
Review
Matrix proteolysis mediated by MT1-MMP facilitates the invasive migration of tumor cells in dense tissues, which otherwise get trapped in the matrix because of limited nuclear deformability. A digest-on-demand response has been identified, which requires nucleus-microtubule linkage through the LINC complex and triggers MT1-MMP surface-exposure to facilitate nucleus movement.
Topics: Cell Movement; Cell Nucleus; Extracellular Matrix; Humans; Lamin Type A; Matrix Metalloproteinase 14; Microtubules; Models, Biological; Neoplasm Invasiveness; Neoplasms; Podosomes
PubMed: 30573318
DOI: 10.1016/j.tcb.2018.11.006 -
Cellular and Molecular Life Sciences :... Jan 2015Podosomes are adhesion and invasion structures that are particularly prominent in cells of the monocytic lineage such as macrophages, dendritic cells, and osteoclasts.... (Review)
Review
Podosomes are adhesion and invasion structures that are particularly prominent in cells of the monocytic lineage such as macrophages, dendritic cells, and osteoclasts. They are multifunctional organelles that combine several key abilities required for cell migration and invasion. The podosome repertoire includes well-established functions such as cell-substrate adhesion, and extracellular matrix degradation, recently discovered abilities such as rigidity and topology sensing as well as antigen sampling, and also more speculative functions such as cell protrusion stabilization and transmigration. Collectively, podosomes not only enable dynamic interactions of cells with their surroundings, they also gather information about the pericellular environment, and are actively involved in its reshaping. This review presents an overview of the current knowledge on podosome composition, architecture, and regulation. We focus in particular on the growing list of podosome functions and discuss the specific properties of podosomes in macrophages, dendritic cells, and osteoclasts. Moreover, this article highlights podosome-related intracellular transport processes, the formation of podosomes in 3D environments as well as potentially podosome-associated diseases involving monocytic cells.
Topics: Animals; Cell Adhesion; Cellular Structures; Dendritic Cells; Extracellular Matrix; Humans; Macrophages; Monocytes; Organelles; Osteoclasts; Signal Transduction
PubMed: 25300510
DOI: 10.1007/s00018-014-1731-z -
Philosophical Transactions of the Royal... Aug 2019Podosomes are a singular category of integrin-mediated adhesions important in the processes of cell migration, matrix degradation and cancer cell invasion. Despite a...
Podosomes are a singular category of integrin-mediated adhesions important in the processes of cell migration, matrix degradation and cancer cell invasion. Despite a wealth of biochemical studies, the effects of mechanical forces on podosome integrity and dynamics are poorly understood. Here, we show that podosomes are highly sensitive to two groups of physical factors. First, we describe the process of podosome disassembly induced by activation of myosin-IIA filament assembly. Next, we find that podosome integrity and dynamics depends upon membrane tension and can be experimentally perturbed by osmotic swelling and deoxycholate treatment. We have also found that podosomes can be disrupted in a reversible manner by single or cyclic radial stretching of the substratum. We show that disruption of podosomes induced by osmotic swelling is independent of myosin-II filaments. The inhibition of the membrane sculpting protein, dynamin-II, but not clathrin, resulted in activation of myosin-IIA filament formation and disruption of podosomes. The effect of dynamin-II inhibition on podosomes was, however, independent of myosin-II filaments. Moreover, formation of organized arrays of podosomes in response to microtopographic cues (the ridges with triangular profile) was not accompanied by reorganization of myosin-II filaments. Thus, mechanical elements such as myosin-II filaments and factors affecting membrane tension/sculpting independently modulate podosome formation and dynamics, underlying a versatile response of these adhesion structures to intracellular and extracellular cues. This article is part of a discussion meeting issue 'Forces in cancer: interdisciplinary approaches in tumour mechanobiology'.
Topics: Cell Movement; Humans; Nonmuscle Myosin Type IIA; Podosomes; Tumor Cells, Cultured
PubMed: 31431172
DOI: 10.1098/rstb.2018.0228 -
Drug Resistance Updates : Reviews and... Jul 2018Dissemination of cancer cells from the primary tumor and their spread to distant sites of the body is the leading cause of mortality in metastatic cancer patients.... (Review)
Review
Dissemination of cancer cells from the primary tumor and their spread to distant sites of the body is the leading cause of mortality in metastatic cancer patients. Metastatic cancer cells invade surrounding tissues and blood vessels by forming F-actin-rich protrusions known as invadopodia, which degrade the extracellular matrix and enable invasion of tumor cells through it. Invadopodia have now been observed in vivo, and recent evidence demonstrates direct molecular links between assembly of invadopodia and cancer metastasis in both mouse models and in human patients. While significant progress has been achieved in the last decade in understanding the molecular mechanisms and signaling pathways regulating invadopodia formation and function, the application of this knowledge to development of prognostic and therapeutic approaches for cancer metastasis has not been discussed before. Here, we provide a detailed overview of current prognostic markers and tests for cancer metastasis and discuss their advantages, disadvantages, and their predicted efficiency. Using bioinformatic patient database analysis, we demonstrate, for the first time, a significant correlation between invadopodia-associated genes to breast cancer metastasis, suggesting that invadopodia could be used as both a prognostic marker and as a therapeutic target for blocking cancer metastasis. We include here a novel network interaction map of invadopodia-associated proteins with currently available inhibitors, demonstrating a central role for the recently identified EGFR-Pyk2-Src-Arg-cortactin invadopodial pathway, to which re-purposing of existent inhibitors could be used to block breast cancer metastasis. We then present an updated overview of current cancer-related clinical trials, demonstrating the negligible number of trials focusing on cancer metastasis. We also discuss the difficulties and complexity of performing cancer metastasis clinical trials, and the possible development of anti-metastasis drug resistance when using a prolonged preventive treatment with invadopodia inhibitors. This review presents a new perspective on invadopodia-mediated tumor invasiveness and may lead to the development of novel prognostic and therapeutic approaches for cancer metastasis.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Movement; Drug Design; Female; Humans; Molecular Targeted Therapy; Neoplasm Invasiveness; Neoplasm Metastasis; Podosomes; Signal Transduction
PubMed: 30075834
DOI: 10.1016/j.drup.2018.05.002