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The Journal of Cell Biology Apr 2016Podosomes are dynamic cell adhesions that are also sites of extracellular matrix degradation, through recruitment of matrix-lytic enzymes, particularly of matrix...
Podosomes are dynamic cell adhesions that are also sites of extracellular matrix degradation, through recruitment of matrix-lytic enzymes, particularly of matrix metalloproteinases. Using total internal reflection fluorescence microscopy, we show that the membrane-bound metalloproteinase MT1-MMP is enriched not only at podosomes but also at distinct "islets" embedded in the plasma membrane of primary human macrophages. MT1-MMP islets become apparent upon podosome dissolution and persist beyond podosome lifetime. Importantly, the majority of MT1-MMP islets are reused as sites of podosome reemergence. siRNA-mediated knockdown and recomplementation analyses show that islet formation is based on the cytoplasmic tail of MT1-MMP and its ability to bind the subcortical actin cytoskeleton. Collectively, our data reveal a previously unrecognized phase in the podosome life cycle and identify a structural function of MT1-MMP that is independent of its proteolytic activity. MT1-MMP islets thus act as cellular memory devices that enable efficient and localized reformation of podosomes, ensuring coordinated matrix degradation and invasion.
Topics: Actin Cytoskeleton; Cell Membrane; Cell Movement; Cells, Cultured; Extracellular Matrix; Humans; Macrophages; Matrix Metalloproteinase 14; Matrix Metalloproteinases; Podosomes; RNA, Small Interfering
PubMed: 27069022
DOI: 10.1083/jcb.201510043 -
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 -
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 -
PloS One 2011Podosomes, important structures for adhesion and extracellular matrix degradation, are claimed to be involved in cell migration. In addition, podosomes are also reported...
Podosomes, important structures for adhesion and extracellular matrix degradation, are claimed to be involved in cell migration. In addition, podosomes are also reported to be of importance in tissue remodelling, e.g., in osteoclast-mediated bone resorption. Podosomes are highly dynamic actin-filament scaffolds onto which proteins important for their function, such as matrix metallo-proteases and integrins, attach. The dynamics of the podosomes require the action of many proteins regulating actin assembly and disassembly. One such protein, gelsolin, which associates to podosomes, has been reported to be important for podosome formation and function in osteoclasts. However, podosome-like structures have been reported in gelsolin-deficient dendritic cells, but the identity of these structures was not confirmed, and their dynamics and function was not investigated. Like many other cells, dendritic cells of the immune system also form matrix degrading podosomes. In the present study, we show that dendritic cells form podosomes independently of gelsolin, that there are no major alterations in their dynamics of formation and disassembly, and that they exhibit matrix-degrading function. Furthermore, we found that gelsolin is not required for TLR4-induced podosome disassembly. Thus, the actin cytoskeleton of podosomes involved in dendritic cell extracellular matrix degradation appears to be regulated differently than the cytoskeleton in podosomes of osteoclasts mediating bone resorption.
Topics: Actins; Animals; Blotting, Western; Cells, Cultured; Cytoskeleton; Dendritic Cells; Extracellular Matrix; Female; Gelsolin; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout
PubMed: 21779330
DOI: 10.1371/journal.pone.0021615 -
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 -
Cancer Letters Feb 2024Growing evidence has suggested that increased matrix stiffness can significantly strengthen the malignant characteristics of hepatocellular carcinoma (HCC) cells....
Growing evidence has suggested that increased matrix stiffness can significantly strengthen the malignant characteristics of hepatocellular carcinoma (HCC) cells. However, whether and how increased matrix stiffness regulates the formation of invadopodia in HCC cells remain largely unknown. In the study, we developed different experimental systems in vitro and in vivo to explore the effects of matrix stiffness on the formation of invadopodia and its relevant molecular mechanism. Our results demonstrated that increased matrix stiffness remarkably augmented the migration and invasion abilities of HCC cells, upregulated the expressions of invadopodia-associated genes and enhanced the number of invadopodia. Two regulatory pathways contribute to matrix stiffness-driven invadopodia formation together in HCC cells, including direct triggering invadopodia formation through activating integrin β1 or Piezo1/ FAK/Src/Arg/cortactin pathway, and indirect stimulating invadopodia formation through improving EGF production to activate EGFR/Src/Arg/cortactin pathway. Src was identified as the common hub molecule of two synergistic regulatory pathways. Simultaneously, activation of integrin β1/RhoA/ROCK1/MLC2 and Piezo1/Ca/MLCK/MLC2 pathways mediate matrix stiffness-reinforced cell migration. This study uncovers a new mechanism by which mechanosensory pathway and biochemical signal pathway synergistically regulate the formation of invadopodia in HCC cells.
Topics: Humans; Carcinoma, Hepatocellular; Cortactin; Podosomes; Liver Neoplasms; Integrin beta1; Extracellular Matrix; Cell Line, Tumor; Neoplasm Invasiveness; rho-Associated Kinases
PubMed: 38145655
DOI: 10.1016/j.canlet.2023.216597 -
European Journal of Cell Biology Oct 2014Podosomes and invadopodia, collectively known as invadosomes, are specialized cell-matrix contacts with an inherent ability to degrade extracellular matrix. Their... (Review)
Review
Podosomes and invadopodia, collectively known as invadosomes, are specialized cell-matrix contacts with an inherent ability to degrade extracellular matrix. Their occurrence in either normal (podosomes) or cancer cells (invadopodia) is thus traditionally associated with cell invasiveness and tissue remodelling. These specialized micro-domains of the plasma membrane are characterized by enrichment of F-actin, cortactin and metalloproteases. Recent developments in the field show that, under some circumstances, vascular endothelial cells (ECs) can be induced to form this kind of peculiar structures. Cultured ECs contain either 0.5-1-μm-wide individual podosomes or 5 to 10 μm wide ring-like clusters of podosomes (podosome rosettes). The formation of individual podosomes or podosome rosettes in ECs can be induced by soluble factors, such as TGFβ, VEGF, TNFα or pharmacological agents, such as phorbol esters. Recently, the evidence of the existence of such structures in vascular endothelium has been provided by ex vivo observation. Endothelial podosome rosettes have recently been functionally linked to arterial remodelling and sprouting angiogenesis. Concerted efforts aim now at confirming the relevance of endothelial podosomes in these patho-physiological processes in vivo. In the current review, we will introduce some general considerations regarding ECs in the vascular system. From there on, we will review the various EC types where podosomes have been described and the state-of-art knowledge hitherto generated regarding endothelial podosome features.
Topics: Animals; Cell Surface Extensions; Endothelial Cells; Humans; Inflammation; Ischemia; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic
PubMed: 25199436
DOI: 10.1016/j.ejcb.2014.07.009 -
Biochimica Et Biophysica Acta.... Apr 2019Extensive in vitro studies have described podosomes as actin-based structures at the plasma membrane, connecting the cell with its extracellular matrix and endowed with... (Review)
Review
Extensive in vitro studies have described podosomes as actin-based structures at the plasma membrane, connecting the cell with its extracellular matrix and endowed with multiple capabilities. Contractile actin-myosin cables assemble them into a network that constitutes a multifaceted cellular superstructure taking different forms - with common characteristics - but manifesting different properties depending on the context of study. Their morphology and their role in cell functioning and behavior are therefore now apprehended in in vivo or in vitro situations relevant to physiological processes. We focus here on three of them, namely: macrophage migration, antigen presentation by dendritic cells and endothelial cell sprouting during angiogenesis to highlight the characteristics of podosomes and their functioning shaped by the microenvironment.
Topics: Antigen Presentation; Cell Membrane; Cell Movement; Dendritic Cells; Endothelium, Vascular; Gene Expression; Macrophages; Neovascularization, Physiologic; Podosomes; Signal Transduction
PubMed: 30594495
DOI: 10.1016/j.bbamcr.2018.12.009 -
Trends in Cell Biology Aug 2017Invadopodia are a subset of invadosomes that are implicated in the integration of signals from the tumor microenvironment to support tumor cell invasion and... (Review)
Review
Invadopodia are a subset of invadosomes that are implicated in the integration of signals from the tumor microenvironment to support tumor cell invasion and dissemination. Recent progress has begun to define how tumor cells regulate the plasticity necessary for invadopodia to assemble and function efficiently in the different microenvironments encountered during dissemination in vivo. Exquisite mapping by many laboratories of the pathways involved in integrating diverse invadopodium initiation signals, from growth factors, to extracellular matrix (ECM) and cell-cell contact in the tumor microenvironment, has led to insight into the molecular basis of this plasticity. Here, we integrate this new information to discuss how the invadopodium is an important conductor that orchestrates tumor cell dissemination during metastasis.
Topics: Animals; Cell Communication; Cell Movement; Extracellular Matrix; Humans; Neoplasm Invasiveness; Neoplasms; Podosomes; Tumor Microenvironment
PubMed: 28412099
DOI: 10.1016/j.tcb.2017.03.003 -
Cell Adhesion & Migration 2014Podosomes are small, circular adhesions formed by cells such as osteoclasts, macrophages, dendritic cells, and endothelial cells. They comprise a protrusive actin core... (Review)
Review
Podosomes are small, circular adhesions formed by cells such as osteoclasts, macrophages, dendritic cells, and endothelial cells. They comprise a protrusive actin core module and an adhesive ring module composed of integrins and cytoskeletal adaptor proteins such as vinculin and talin. Furthermore, podosomes are associated with an actin network and often organize into large clusters. Recent results from our laboratory and others have shed new light on podosome structure and dynamics, suggesting a revision of the classical "core-ring" model. Also, these studies demonstrate that the adhesive and protrusive module are functionally linked by the actin network likely facilitating mechanotransduction as well as providing feedback between these two modules. In this commentary, we briefly summarize these recent advances with respect to the knowledge on podosome structure and discuss force distribution mechanisms within podosomes and their emerging role in mechanotransduction.
Topics: Actins; Animals; Cell Adhesion; Cell Movement; Humans; Mechanotransduction, Cellular
PubMed: 24658050
DOI: 10.4161/cam.28182