MMP proteolytic activity regulates cancer invasiveness by modulating integrins

Das, Alakesh; Monteiro, Melissa; Barai, Amlan; Kumar, Sandeep; Sen, Shamik

doi:10.1038/s41598-017-14340-w

Cited by 119 publications

(87 citation statements)

References 58 publications

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“…MMP and ADAM family members contribute to many physiological and pathological processes by mediating cellular proliferation, migration, invasion, differentiation, apoptosis, inflammation, and angiogenesis by degrading a variety of ECM proteins including Type I and IV collagens, laminin, fibronectin, fibrinogen, and proteoglycans (Roy et al, , ; Murphy, , ; Murphy and Nagase, ; Hadler‐Olsen et al, ; Bonnans et al, ; Yang et al, ; Das et al, ). Proteolysis of basement membrane components is directly associated with cancer cell invasion by cleavage and release of cryptic peptides or neoepitopes that alter cell‐matrix interactions and are involved in signaling between basement membrane and cancer cells (Schenk and Quaranta, ).…”

Section: Functional Roles Of Mmps and Adams In The Tumor Microenvironmentioning

confidence: 99%

Metalloproteinases and their roles in human cancer

Roy

Morad

Jedinak

et al. 2019

The Anatomical Record

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It is now widely appreciated that members of the matrix metalloproteinase (MMP) family of enzymes play a key role in cancer development and progression along with many of the hallmarks associated with them. The activity of these enzymes has been directly implicated in extracellular matrix remodeling, the processing of growth factors and receptors, the modulation of cell migration, proliferation, and invasion, the epithelial to mesenchymal transition, the regulation of immune responses, and the control of angiogenesis. Certain MMP family members have been validated as biomarkers of a variety of human cancers including those of the breast, brain, pancreas, prostate, ovary, and others. The related metalloproteinases, the A disintegrin and metalloproteinases (ADAMs), share a number of these functions as well. Here, we explore these essential metalloproteinases and some of their disease-associated activities in detail as well as some of their complementary translational potential. Anat Rec, 303:1557-1572, 2020.Matrix metalloproteinases (MMPs) are a multigene family of metal-dependent endopeptidases that play important and diverse roles in normal physiological and pathological processes. The classic domain structure of MMP family members can be found in Figure 1 (Roy et al., 2009). MMPs include an amino-terminal signal peptide required for secretion, a pro-domain that mediates latency via a cysteine-switch mechanism and a Zn 2+ -dependent catalytic domain that is responsible for enzymatic function. A majority of MMPs also contain a C-terminal hemopexinlike domain that provides substrate specificity. MMP activity is the rate-limiting step in extracellular matrix (ECM) degradation and it can regulate the activity of other proteases, growth factors, cytokines, and cell-surface ligands

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Section: Functional Roles Of Mmps and Adams In The Tumor Microenvironmentioning

confidence: 99%

Metalloproteinases and their roles in human cancer

Roy

Morad

Jedinak

et al. 2019

The Anatomical Record

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“…Second, the GIV•Exo70 interaction impacts our understanding of the pro-metastatic role of GIV in diverse cancers and how it impacts key tumor cell behaviors that are dependent on proteolysis. Because GIV modulates integrin/FAK signaling via G protein intermediates Leyme et al, 2015;Lopez-Sanchez et al, 2015b), and because integrins and MT1-MMPs regulate each other's activity, trafficking and signaling to integrate events in the extracellular milieu (Baciu et al, 2003;Das et al, 2017;Galvez et al, 2002;Gonzalo et al, 2010;Shi and Sottile, 2011;Zigrino et al, 2001), it is possible that GIV's C-terminus may help in such process of integration. But to begin to entertain that possibility or test it, an in-depth insight into how GIV binds integrins, and how such binding impacts the GIV•Exo70 interaction is required first.…”

Section: Discussionmentioning

confidence: 99%

GIV/Girdin and Exo70 Constitute the Core of the Mammalian Polarized Exocytic Machinery

Rohena

Rajapakse

et al. 2019

Preprint

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Graphic Abstract: Schematic comparing the components of polarized exocytosis, i.e., the major polarity scaffold in yeast (Bem1p; left) and humans (Girdin; right) and the various cellular components and signaling mechanisms that are known to converge on them. The eTOC blurb (50 words)Polarized exocytosis is a precision-controlled process that is enhanced in disease states, e.g., cancer invasion; what imparts polarity was unknown. Authors reveal how the process underwent an evolutionary upgrade from yeast to humans by pinpointing GIV/Girdin as the polarity scaffold which orchestrates the exocytosis of matrix metalloproteases during cell invasion. HIGHLIGHTS• GIV (human) and Bem1p (yeast) bind Exo70; are required for exocytosis • GIV binds and aids PM localization Exo70 via a conserved short linear motif• Binding facilitates MT1-MMP delivery to podosomes, ECM degradation, invasion• Regulatory control over polarized exocytosis is upgraded during evolution SUMMARY Polarized exocytosis is a fundamental process by which membrane and cargo proteins are delivered to the plasma membrane with precise spatial control; it is essential for cell growth, morphogenesis, and migration.Although the need for the octameric exocyst complex is conserved from yeast to humans, what imparts spatial control is known only in yeast, i.e., a polarity scaffold without mammalian homolog, called Bem1p. We demonstrate that polarity scaffold GIV/Girdin fulfills the key criteria and functions of its yeast counterpart Bem1p. Both Bem1p and GIV bind yeast and mammalian Exo70 proteins via similar short-linear interaction motifs, but each preferentially binds its evolutionary counterpart. In cells where this GIV•Exo-70 interaction is selectively disrupted, delivery of the metalloprotease MT1-MMP to podosomes, collagen degradation and haptotaxis through basement membrane matrix were impaired. GIV's interacting partners reveal other components of polarized exocytosis in mammals. Findings not only expose how GIV "upgrades" the exocytic process in mammals, but also how the ability to regulate exocytosis shapes GIV's ability to fuel metastasis.

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“…In order to make the C1 fibrillar, a plugin is applied on the cells which elongate them in axis, random with respect to each other at 0.8 unit volume increment at each MCS till 5. The length-scale of components of ECM (BM and C1) is kept relatively smaller than cancer cells (Das et al, 2017). The lattices with no assigned cell-type or in other words the gaps or the free spaces are assigned cell-type ‘medium’ as a default of the Compucell3D syntax.…”

Section: Methodsmentioning

confidence: 99%

An interplay between reaction-diffusion and cell-matrix adhesion regulates multiscale invasion in early breast carcinomatosis

Pally

Pramanik

Bhat

2019

Preprint

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Equal contribution.The progression of cancer in the breast involves multiple reciprocal interactions between malignantly transformed epithelia, surrounding untransformed but affected stromal cells, and the extracellular matrix (ECM) that is remodelled during the process. A quantitative understanding of the relative contribution of such interactions to phenotypes associated with cancer cells can be arrived at through the construction of increasingly complex experimental and computational models. Herein, we introduce a multiscale 3D organo-and patho-typic model that approximates, to an unprecedented extent, the histopathological complexity of a tumor disseminating into its surrounding stromal milieu via both bulk and solitary motility dynamics. End-point and time-lapse microscopic observations of this model allow us to study the earliest steps of cancer invasion as well as the dynamical interactions between the epithelial and stromal compartments. We then construct an agent-based Cellular Potts model that incorporates constituents of the experimental model, as well as places them in similar spatial arrangements. The computational model, which comprises adhesion between cancer cells and the matrices, cell proliferation and apoptosis, and matrix remodeling through reaction-diffusion-based morphogen dynamics, is first trained to phenocopy controls run with the experimental model, wherein one or the other matrices have been removed. The trained computational model successfully predicts phenotypes of the experimental counterparts that are subjected to pharmacological treatments (inhibition of N-linked glycosylation and matrix metalloproteinase activity) and scaffold modulation (alteration of collagen density). Our results suggest that specific permissive regimes of cell-cell and cell-matrix adhesions operating in the context of a reaction-diffusionregulated ECM dynamics, promote multiscale invasion of breast cancer cells and determine the extent to which they migrate through their surrounding stroma. Preparation of cancer cell clusters:Normal/cancer cells were trypsinized using 1:5 diluted 0.25% Trypsin & 0.02% EDTA (HiMedia, TCL007). 30,000 cells per 200 μ L of defined medium (Blaschke et al., 1994) supplemented with 4% rBM (Corning, 354230) were cultured on 3% polyHEMA (Sigma, P3932) coated 96 well plate for 48 hours in a 37 o C humidified incubator with 5% carbon dioxide. 3D invasion assay:rBM-coated clusters were collected into 1.5 mL tubes, centrifuged briefly and supernatant is removed. Acid-extracted rat tail collagen (Gibco, A1048301) was neutralized on ice in the presence of 10X DMEM with 0.1N NaOH such that the final concentration of the collagen is 1 mg/mL. Pellet of clusters was resuspended in 50 μ L of neutralized collagen and seeded in 8-well chambered cover glass (Eppendorf 0030742036) and supplemented with defined medium. 3D cultures were grown in a 37 o C humidified incubator with 5% carbon dioxide. Processing of 3D invasive clusters:3D invasion cultures were washed with phosphate buffered saline pH 7...

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MMP proteolytic activity regulates cancer invasiveness by modulating integrins

Cited by 119 publications

References 58 publications

Metalloproteinases and their roles in human cancer

Metalloproteinases and their roles in human cancer

GIV/Girdin and Exo70 Constitute the Core of the Mammalian Polarized Exocytic Machinery

An interplay between reaction-diffusion and cell-matrix adhesion regulates multiscale invasion in early breast carcinomatosis

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