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Epithelial-to-mesenchymal transition (EMT) recapitulates metastasis and can be induced in vitro through transforming growth factor (TGF)-β signaling. A role for MMP activity in glioblastoma multiforme has been ascribed to EMT, but the molecular crosstalk between TGF-β signaling and membrane type 1 MMP (MT1-MMP) remains poorly understood. Here, the expression of common EMT biomarkers, induced through TGF-β and the MT1-MMP inducer concanavalin A (ConA), was explored using RNA-seq analysis and differential gene arrays in human U87 glioblastoma cells. TGF-β triggered SNAIL and fibronectin expressions in 2D-adherent and 3D-spheroid U87 glioblastoma cell models. Those inductions were antagonized by the TGF-β receptor kinase inhibitor galunisertib, the JAK/STAT inhibitors AG490 and tofacitinib, and by the diet-derived epigallocatechin gallate (EGCG). Transient gene silencing of MT1-MMP prevented the induction of SNAIL by ConA and abrogated TGF-β-induced cell chemotaxis. Moreover, ConA induced STAT3 and Src phosphorylation, suggesting these pathways to be involved in the MT1-MMP-mediated signaling axis that led to SNAIL induction. Our findings highlight a new signaling axis linking MT1-MMP to TGF-β-mediated EMT-like induction in glioblastoma cells, the process of which can be prevented by the diet-derived EGCG.

Pathological angiogenesis contributes to cancer progression and chronic inflammatory diseases. In inflammatory bowel disease, the microvasculature expands by intussusceptive angiogenesis (IA), a poorly characterized mechanism involving increased blood flow and splitting of pre‐existing capillaries. In this report, mice lacking the protease MT1‐MMP in endothelial cells (MT1 iΔ EC ) presented limited IA in the capillary plexus of the colon mucosa assessed by 3D imaging during 1% DSS‐induced colitis. This resulted in better tissue perfusion, preserved intestinal morphology, and milder disease activity index. Combined in vivo intravital microscopy and lentiviral rescue experiments with in vitro cell culture demonstrated that MT1‐MMP activity in endothelial cells is required for vasodilation and IA, as well as for nitric oxide production via binding of the C‐terminal fragment of MT1‐MMP substrate thrombospondin‐1 (TSP1) to CD47/αvβ3 integrin. Moreover, TSP1 levels were significantly higher in serum from IBD patients and in vivo administration of an anti‐MT1‐MMP inhibitory antibody or a nonamer peptide spanning the αvβ3 integrin binding site in TSP1 reduced IA during mouse colitis. Our results identify MT1‐MMP as a new actor in inflammatory IA and a promising therapeutic target for inflammatory bowel disease. Synopsis Inflammatory bowel disease comprising ulcerative colitis and Crohn's disease does not have a universal efficient therapy. This study identifies the molecular axis MT1‐MMP/thrombospondin‐1/αvβ3 integrin/nitric oxide as a target to reduce inflammatory intussusceptive angiogenesis and improve colitis. Early expansion of the capillaries in the intestinal mucosa during colitis was caused by intussusceptive/splitting angiogenesis (IA). Deletion of the protease MT1‐MMP from endothelial cells reduced IA and colitis severity. Thrombospondin‐1 (TSP1) processing by MT1‐MMP promoted nitric oxide production, vasodilation and IA. High levels of TSP1 were found in sera from patients suffering low active IBD. Targeting MT1‐MMP/TSP1/αvβ3 integrin/nitric oxide pathway by monoclonal antibodies or minipump‐delivered peptides decreased IA and ameliorates colitis. Graphical Abstract Inflammatory bowel disease comprising ulcerative colitis and Crohn's disease does not have a universal efficient therapy. This study identifies the molecular axis MT1‐MMP/thrombospondin‐1/αvβ3 integrin/nitric oxide as a target to reduce inflammatory intussusceptive angiogenesis and improve colitis.

Small‐cell lung cancer (SCLC) is an aggressive tumor characterized by the frequent development of distant metastases. This study aimed to explore the mechanism of SCLC metastasis using an originally developed orthotopic transplantation model with DMS273 cells. An analysis of G3H cells, a highly metastatic subline of DMS273 cells, revealed that claudin‐11 promotes the invasive and metastatic ability of the cells. Further analysis revealed that membrane type 1‐matrix metalloproteinase (MT1‐MMP), which degrades a wide range of extracellular matrix components, was coprecipitated with claudin‐11. Gelatin zymography revealed that claudin‐11 enhanced MT1‐MMP activity, and MT1‐MMP silencing suppressed the invasive and metastatic ability of G3H cells. Moreover, in MT1‐MMP silencing DMS273 cells, the enhancement of invasion and metastatic potential induced by CLDN11 overexpression was abolished. These results demonstrate that claudin‐11 enhances the invasive capacity of the cells by activating MT1‐MMP, which promotes metastatic formation in the orthotopic transplantation model. Additionally, claudin‐11 expression was detected in SCLC tumor samples, and higher expression of CLDN11 correlated with poor prognosis in patients with SCLC. These findings suggest that the claudin‐11/MT1‐MMP axis plays an important role in SCLC pathogenesis. Claudin‐11 is a tight junction protein, and its role in small‐cell lung cancer (SCLC) remains unclear. This study showed that claudin‐11 was significantly upregulated in a highly metastatic subline of DMS273 SCLC cells, promoting cell invasion and metastasis through the activation of MT1‐MMP. Furthermore, claudin‐11 expression was detected in some SCLC tumors, and its expression was associated with poor patient prognosis.

Cancer cell invasion through tissue barriers is the intrinsic feature of metastasis, the most life-threatening aspect of cancer. Detailed observation and analysis of cancer cell behaviour in a 3D environment is essential for a full understanding of the mechanisms of cancer cell invasion. The inherent limits of optical microscopy resolution do not allow to for in-depth observation of intracellular structures, such as invadopodia of invading cancer cells. The required resolution can be achieved using electron microscopy techniques such as FIB-SEM. However, visualising cells in a 3D matrix using FIB-SEM is challenging due to difficulties with localisation of a specific cell deep within the resin block. We have developed a new protocol based on the near-infrared branding (NIRB) procedure that extends the pattern from the surface grid deep inside the resin. This 3D burned pattern allows for precise trimming followed by targeted 3D FIB-SEM. Here we present detailed 3D CLEM results combining confocal and FIB-SEM imaging of cancer cell invadopodia that extend deep into the collagen meshwork.

An artificial receptor for proMMP‐9 was created by fusing tissue inhibitor of MMP‐1 (TIMP‐1) with type II transmembrane mosaic serine protease (MSP‐T1). Expression of MSP‐T1 in 293T cells induced binding of proMMP‐9, which was processed by MMP‐2 activated by membrane type 1 MMP (MT1‐MMP). HT1080 cells transfected with the MSP‐T1 gene produced activated MMP‐9 in collagen gel, and addition of proMMP‐2 to the culture augmented it, which resulted in intensive collagen digestion. These cells metastasized into chick embryonic liver more than control cells. Treatment of HT1080 cells with concanavalin A in the presence of exogenous proMMP‐2 induced activation of not only proMMP‐2 but also proMMP‐9. Knockdown of MT1‐MMP or TIMP‐2 expression with siRNA suppressed activation of both proMMP‐2 and proMMP‐9. Transfection of TIMP‐1 siRNA suppressed cell binding and activation of proMMP‐9, but not proMMP‐2 activation. Knockdown of a disintegrin and metalloproteinase 10 (ADAM10) expression reduced cell binding and processing of proMMP‐9. These results suggest that proMMP‐9, which binds to a receptor complex containing TIMP‐1 and ADAM10, is activated by the MT1‐MMP/MMP‐2 axis, and MMP‐9 thus activated stimulates cellular proteolysis and metastasis. ProMMP‐9 which binds to a receptor complex containing TIMP‐1 and ADAM10 is activated by MT1‐MMP/MMP‐2 axis. MMP‐9 thus activated stimulates cellular proteolysis and metastasis.

Strategies to develop cancer therapies using inhibitors that target matrix metalloproteinases (MMPs), particularly membrane type‐1 MMP (MT1‐MMP), have failed. This is predominantly attributed to the specificity of MMP inhibitors and numerous functions of MMPs; therefore, targeting substrates with such broad specificity can lead to off‐target effects. Thus, new drug development for cancer therapeutics should focus on the ability of MT1‐MMP to break down substrates, such as functional cell membrane proteins, to regulate the functions of these proteins that promote tumor malignancy. In this review, we discuss the mechanism by which proteolysis of cell surface proteins by MT1‐MMP promotes progression of malignant tumor cells. In addition, we discuss the two protein fragments generated by limited cleavage of erythropoietin‐producing hepatoma receptor tyrosine kinase A2 (EphA2‐NF, ‐CF), which represent a promising basis for developing new cancer therapies and diagnostic techniques. Cell surface proteolysis by MT1‐MMP promotes malignant progression of tumor cells and may be a diagnostic and theputic ratget for cancers.

Membrane‐type 1 matrix metalloproteinase (MT1‐MMP) is expressed in different types of invasive and proliferative cells, including cancer cells and stromal cells. MT1‐MMP cleaves extracellular matrix proteins, membrane proteins and other pericellular proteins, thereby changing the cellular microenvironment and regulating signal activation. Critical roles of protease activity in cancer cell proliferation, invasion and metastasis have been demonstrated by many groups. MT1‐MMP also has a non‐protease activity in that it inhibits the oxygen‐dependent suppression of hypoxia‐inducible factors (HIFs) via Munc18‐1‐interacting protein 3 (Mint3) and thereby enhances the expression of HIF target genes. Elevated HIF activity in MT1‐MMP‐expressing cancer cells is a fundamental mechanism underlying the Warburg effect, a well‐known phenomenon where malignant cancer cells exhibit a higher rate of glucose metabolism. Because specific intervention of HIF activation by MT1‐MMP suppresses tumor formation by cancer cells in mice, both the proteolytic and non‐proteolytic activities of MT1‐MMP are important for tumor malignancy and function in an integrated manner. In this review, we summarize recent findings relating to how MT1‐MMP activates HIF and its effects on cancer cells and stromal cells. In cancer cells and activated stromal cells, MT1‐MMP promotes invasion, motility, and proliferation in a proteolytic manner. MT1‐MMP also activates hypoxia‐inducible factor and thereby promotes the Warburg effect and angiogenesis in a non‐proteolytic manner. Thus, MT1‐MMP integrates malignant traits of cancer.

MT1‐matrix metalloproteinase (MT1‐MMP) is one of the most critical factors in the invasion machinery of tumor cells. Subcellular localization to invasive structures is key for MT1‐MMP proinvasive activity. However, the mechanism driving this polarized distribution remains obscure. We now report that polarized exocytosis of MT1‐MMP occurs during MDA‐MB‐231 adenocarcinoma cell migration into collagen type I three‐dimensional matrices. Polarized trafficking of MT1‐MMP is triggered by β1 integrin‐mediated adhesion to collagen, and is required for protease localization at invasive structures. Localization of MT1‐MMP within VSV‐G/Rab8‐positive vesicles, but not in Rab11/Tf/TfRc‐positive compartment in invasive cells, suggests the involvement of the exocytic traffic pathway. Furthermore, constitutively active Rab8 mutants induce MT1‐MMP exocytic traffic, collagen degradation and invasion, whereas Rab8‐ but not Rab11‐knockdown inhibited these processes. Altogether, these data reveal a novel pathway of MT1‐MMP redistribution to invasive structures, exocytic vesicle trafficking, which is crucial for its role in tumor cell invasiveness. Mechanistically, MT1‐MMP delivery to invasive structures, and therefore its proinvasive activity, is regulated by Rab8 GTPase.

Under conditions of starvation, normal and tumor epithelial cells can rewire their metabolism toward the consumption of extracellular proteins, including extracellular matrix‐derived components as nutrient sources. The mechanism of pericellular matrix degradation by starved cells has been largely overlooked. Here it is shown that matrix degradation by breast and pancreatic tumor cells and patient‐derived xenograft explants increases by one order of magnitude upon amino acid and growth factor deprivation. In addition, it is found that collagenolysis requires the invadopodia components, TKS5, and the transmembrane metalloproteinase, MT1‐MMP, which are key to the tumor invasion program. Increased collagenolysis is controlled by mTOR repression upon nutrient depletion or pharmacological inhibition by rapamycin. The results reveal that starvation hampers clathrin‐mediated endocytosis, resulting in MT1‐MMP accumulation in arrested clathrin‐coated pits. The study uncovers a new mechanism whereby mTOR repression in starved cells leads to the repurposing of abundant plasma membrane clathrin‐coated pits into robust ECM‐degradative assemblies. Cancer cells catabolize extracellular matrix (ECM) components to maintain growth when nutrients are depleted. This study reports that tumor cells repurpose the invadopodia‐, protease‐dependent program to elicit a massive ECM degradation mechanism, under regulation by mechanistic target of rapamycin complex 1. Nutrient scarcity blocks endocytosis of membrane type 1‐matrix metalloproteinase converting arrested clathrin‐coated pits into powerful matrix degradation units.

Introduction Despite the increased understanding of treadmill training on angiogenesis of stroke patients, its mechanism is not clearly known. The metalloproteinase membrane type 1‐metalloprotease (MT1‐MMP) promotes the regeneration of the peripheral vessels but seldom research on the regeneration of cerebral blood vessels. This study was designed to investigate the effects of treadmill exercise on angiogenesis and MT1‐MMP expression after cerebral ischemia in rats. Methods The adult male Sprague Dawley(SD) rats were randomly divided into three groups: sham operation group, the middle cerebral artery occlusion group(MCAO) and middle cerebral artery occlusion group(MCAO)+exercise group. In 4d, 7d or 14d after MCAO, respectively, the rats’ neurological function was evaluated by the modified neurologic severity scores (mNSS); the microvessel numbers in areas surrounding cerebral ischemia were counted with Microvessel Density(MVD)analysis; the levels of MT1‐MMP and reversion‐inducing cysteine‐rich protein with Kazalmotifs (RECK) were detected by Western‐blot and immunohistochemical method. Results Compared with MCAO group, the number of capillaries and the level of MT1‐MMP expression around the area of cerebral ischemia were significantly increased in each exercise group (p < 0.05), while the level of RECK expression and the scores of mNSS in each exercise group were significantly decreased (p < 0.05). Conclusion This study suggested that treadmill exercise training can significantly promote angiogenesis and improve neurological function after cerebral ischemia. Its mechanism may be related to the upgraduation of the MT1‐MMP expression in brain microvessels surrounding area of the ischemic rat. There are a lot of evidences showing that MT1‐MMP promotes the regeneration of the peripheral vessels but seldom research on the regeneration of cerebral blood vessels.In this study, we investigated the the effects of treadmill exercise on angiogenesis and the metalloproteinase membrane type 1‐metalloprotease (MT1‐MMP)expression after cerebral ischemia in rats to readmill exercise training can significantly promote angiogenesis and improve neurological function after cerebral ischemia.