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Genome-wide analysis of control and MMP-14 (MT1-MMP) expressing MCF-7 cells growing in three-dimensional (3D) type I collagen gels versus monolayer cell culture conditions

ABSTRACT: In order to investigate the impact of MMP-14 (MT1-MMP) and three-dimensional (3D) culture conditions on the transcriptomes of a human breast adenocarcinoma cell line, we performed a microarray analysis from RNAs isolated from MCF-7 cells expressing either an empty vector (CTRL) or human MMP-14 cDNA (MT1) in monolayer (2D) and 3D collagen (3D Col) growth conditions. MCF-7 cells were stably transfected with either an empty vector (pcDNA3.1/Zeo) or human MMP-14 cDNA (pcDNA3.1-MMP-14/Zeo). Cells were grown for 24, 48 and 72 hours in three-dimensional (3D) type I collagen gels or in monolayer culture conditions. Cells were then lysed in TRIzol and total RNA was isolated. For each experimental condition, total RNAs isolated from 4 independant biological replicates were pooled.

ORGANISM(S): Homo sapiens

SUBMITTER: Maquoi Erik

PROVIDER: S-ECPF-GEOD-49595 | biostudies-other |

REPOSITORIES: biostudies-other

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Genome-wide analysis of control and MMP-14 (MT1-MMP) expressing MCF-7 cells growing in three-dimensional (3D) type I collagen gels versus monolayer cell culture conditions

2014-12-15 | GSE49595 | GEO

Genome-wide analysis of control and MMP-14 (MT1-MMP) expressing MCF-7 cells growing in three-dimensional (3D) type I collagen gels versus monolayer cell culture conditions

Project description:In order to investigate the impact of MMP-14 (MT1-MMP) and three-dimensional (3D) culture conditions on the transcriptomes of a human breast adenocarcinoma cell line, we performed a microarray analysis from RNAs isolated from MCF-7 cells expressing either an empty vector (CTRL) or human MMP-14 cDNA (MT1) in monolayer (2D) and 3D collagen (3D Col) growth conditions. MCF-7 cells were stably transfected with either an empty vector (pcDNA3.1/Zeo) or human MMP-14 cDNA (pcDNA3.1-MMP-14/Zeo). Cells were grown for 24, 48 and 72 hours in three-dimensional (3D) type I collagen gels or in monolayer culture conditions. Cells were then lysed in TRIzol and total RNA was isolated. For each experimental condition, total RNAs isolated from 4 independant biological replicates were pooled.

2014-12-15 | E-GEOD-49595 | biostudies-arrayexpress

Genome-wide analysis of MCF-7 cells expressing or not MMP-14 (MT1-MMP) growing in monolayer cell culture conditions

2015-12-11 | GSE64320 | GEO

Genome-wide analysis of MCF-7 cells expressing or not MMP-14 (MT1-MMP) growing in monolayer cell culture conditions

Project description:In order to investigate the impact of MMP-14 (MT1-MMP) on the transcriptomes of a human breast adenocarcinoma cell line, we performed a microarray analysis from RNAs isolated from MCF-7 cells expressing either an empty vector (VEC) or human MMP-14 cDNA (MT1) in monolayer growth conditions. MCF-7 cells were stably transfected with either an empty vector (pcDNA3.1/Zeo) or human MMP-14 cDNA (pcDNA3.1-MMP-14/Zeo). Cells were grown for 48 hours in monolayer culture. Cells were then lysed in TRIzol and total RNA was isolated. For each experimental condition, total RNAs isolated from 3 independant biological replicates were pooled.

2015-12-11 | E-GEOD-64320 | biostudies-arrayexpress

A monoclonal antibody interferes with TIMP-2 binding and incapacitates the MMP-2-activating function of multifunctional, pro-tumorigenic MMP-14/MT1-MMP.

Project description:Matrix metalloproteinases (MMPs) and, especially membrane type 1 (MT1)-MMP/MMP-14, are promising drug targets in malignancies. In contrast with multiple small-molecule and protein pan-inhibitors of MT1-MMP cleavage activity, the murine 9E8 monoclonal antibody targets the MMP-2-activating function of cellular MT1-MMP alone, rather than the general proteolytic activity and the pro-migratory function of MT1-MMP. Furthermore, the antibody does not interact in any detectable manner with other members of the membrane type (MT)-MMP family. The mechanism of this selectivity remained unknown. Using mutagenesis, binding and activity assays, and modeling in silico, we have demonstrated that the 9E8 antibody recognizes the MT-loop structure, an eight residue insertion that is specific for MT-MMPs and that is distant from the MT1-MMP active site. The binding of the 9E8 antibody to the MT-loop, however, prevents tissue inhibitor of metalloproteinases-2 (TIMP-2) association with MT1-MMP. As a result, the 9E8 antibody incapacitates the TIMP-2-dependent MMP-2-activating function alone rather than the general enzymatic activity of human MT1-MMP. The specific function of the 9E8 antibody we determined directly supports an essential, albeit paradoxical, role of the protein inhibitor (TIMP-2) in MMP-2 activation via a unique membrane-tethered mechanism. In this mechanism, the formation of a tri-molecular MT1-MMPTIMP-2MMP-2 complex is required for both the capture of the soluble MMP-2 proenzyme by cells and then its well-controlled conversion into the mature MMP-2 enzyme. In sum, understanding of the structural requirements for the 9E8 antibody specificity may pave the way for the focused design of the inhibitory antibodies against other individual MMPs.

| S-EPMC3940861 | biostudies-literature

Self-Assembling Peptide Gels for 3D Prostate Cancer Spheroid Culture.

Project description:Progress in prostate cancer research is presently limited by a shortage of reliable in vitro model systems. The authors describe a novel self-assembling peptide, bQ13, which forms nanofibers and gels useful for the 3D culture of prostate cancer spheroids, with improved cytocompatibility compared to related fibrillizing peptides. The mechanical properties of bQ13 gels can be controlled by adjusting peptide concentration, with storage moduli ranging between 1 and 10 kPa. bQ13's ability to remain soluble at mildly basic pH considerably improved the viability of encapsulated cells compared to other self-assembling nanofiber-forming peptides. LNCaP cells formed spheroids in bQ13 gels with similar morphologies and sizes to those formed in Matrigel or RADA16-I. Moreover, prostate-specific antigen (PSA) is produced by LNCaP cells in all matrices, and PSA production is more responsive to enzalutamide treatment in bQ13 gels than in other fibrillized peptide gels. bQ13 represents an attractive platform for further tailoring within 3D cell culture systems.

| S-EPMC6333502 | biostudies-literature

MMP-14 (MT1-MMP) Is a Biomarker of Surgical Outcome and a Potential Mediator of Hearing Loss in Patients With Vestibular Schwannomas.

Project description:Improved biomarkers are needed for vestibular schwannoma (VS), the most common tumor of the cerebellopontine angle, as existing clinical biomarkers have poor predictive value. Factors such as tumor size or growth rate do not shed light on the pathophysiology of associated sensorineural hearing loss (SNHL) and suffer from low specificity and sensitivity, whereas histological markers only sample a fraction of the tumor and are difficult to ascertain before tumor treatment or surgical intervention. Proteases play diverse and critical roles in tumorigenesis and could be leveraged as a new class of VS biomarkers. Using a combination of in silico, in vitro, and ex vivo approaches, we identified matrixmetalloprotease 14 (MMP-14; also known as MT1-MMP), from a panel of candidate proteases that were differentially expressed through the largest meta-analysis of human VS transcriptomes. The abundance and proteolytic activity of MMP-14 in the plasma and tumor secretions from VS patients correlated with clinical parameters and the degree of SNHL. Further, MMP-14 plasma levels correlated with surgical outcomes such as the extent of resection. Finally, the application of MMP-14 at physiologic concentrations to cochlear explant cultures led to damage to spiral ganglion neuronal fibers and synapses, thereby providing mechanistic insight into VS-associated SNHL. Taken together, MMP-14 represents a novel molecular biomarker that merits further validation in both diagnostic and prognostic applications for VS.

| S-EPMC7424165 | biostudies-literature

Basal localization of MT1-MMP is essential for epithelial cell morphogenesis in 3D collagen matrix.

Project description:The membrane-anchored collagenase membrane type 1 matrix metalloprotease (MT1-MMP) has been shown to play an essential role during epithelial tubulogenesis in 3D collagen matrices; however, its regulation during tubulogenesis is not understood. Here, we report that degradation of collagen in polarized epithelial cells is post-translationally regulated by changing the localization of MT1-MMP from the apical to the basal surface. MT1-MMP predominantly localizes at the apical surface in inert polarized epithelial cells, whereas treatment with HGF induced basal localization of MT1-MMP followed by collagen degradation. The basal localization of MT1-MMP requires the ectodomains of the enzyme because deletion of the MT-loop region or the hemopexin domain inhibited basal localization of the enzyme. TGF? is a well-known inhibitor of tubulogenesis and our data indicate that its mechanism of inhibition is, at least in part, due to inhibition of MT1-MMP localization to the basal surface. Interestingly, however, the effect of TGF? was found to be bi-phasic: at high doses it effectively inhibited basal localization of MT1-MMP, whereas at lower doses tubulogenesis and basal localization of MT1-MMP was promoted. Taken together, these data indicate that basal localization of MT1-MMP is a key factor promoting the degradation of extracellular matrix by polarized epithelial cells, and that this is an essential part of epithelial morphogenesis in 3D collagen.

| S-EPMC4117704 | biostudies-literature

MT1-MMP recruits the ER-Golgi SNARE Bet1 for efficient MT1-MMP transport to the plasma membrane.

Project description:Metastasis is a major cause of cancer-related death. Membrane type 1-matrix metalloproteinase (MT1-MMP) is a critical protease for local invasion and metastasis. MT1-MMP is synthesized in the endoplasmic reticulum (ER) and transported in vesicles to invadopodia, specialized subdomains of the plasma membrane, through secretory and endocytic recycling pathways. The molecular mechanism underlying intracellular transport of MT1-MMP has been extensively studied, but is not fully understood. We show that MT1-MMP diverts the SNARE Bet1 from its function in ER-Golgi transport, to promote MT1-MMP trafficking to the cell surface, likely to invadopodia. In invasive cells, Bet1 is localized in MT1-MMP-positive endosomes in addition to the Golgi apparatus, and forms a novel SNARE complex with syntaxin 4 and endosomal SNAREs. MT1-MMP may also use Bet1 for its export from raft-like structures in the ER. Our results suggest the recruitment of Bet1 at an early stage after MT1-MMP expression promotes the exit of MT1-MMP from the ER and its efficient transport to invadopodia.

| S-EPMC6781441 | biostudies-literature

MT1-MMP dependent repression of the tumor suppressor SPRY4 contributes to MT1-MMP driven melanoma cell motility.

Project description:Metastatic melanoma is the deadliest of all skin cancers. Despite progress in diagnostics and treatment of melanoma, the prognosis for metastatic patients remains poor. We previously showed that Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) is one of the drivers of melanoma metastasis. Classically, MT1-MMP regulates a verity of cellular functions including cell-to-cell interaction and cell-to-matrix communication. Recently, MT1-MMP has been found to also modulate gene expression. To specifically assess MT1-MMP dependent gene regulation in melanoma, microarray gene expression analysis was performed in a melanoma cell line whose metastatic properties depend on the activity of MT1-MMP. We identified the tumor suppressor gene SPRY4 as a new transcriptional target of MT1-MMP that is negatively regulated by the protease. Knockdown of MT1-MMP enhances SPRY4 expression at the mRNA and protein level. SPRY4 expression inversely correlates with that of MT1-MMP in melanoma samples and importantly, correlates with melanoma patient survival. SPRY4 modulates MT1-MMP dependent cell migration such that inhibition of SPRY4 rescues cell migration that has been impaired by MT1-MMP knock down. MT1-MMP decreases SPRY4 in part through an MMP2/RAC1 axis we previously show promotes cell motility downstream of MT1-MMP. These results identify the tumor suppressor SPRY4 as a novel molecular effector of MT1-MMP affecting melanoma cell motility.

| S-EPMC4741782 | biostudies-literature

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