MT1-MMP Activation of TGF-? Signaling Enables Intercellular Activation of an Epithelial-mesenchymal Transition Program in Cancer

Nguyen, Hoang-Lan; Kadam, Pournima; Helkin, Alex; Cao, Kevin; Wu, Song; Samara, Ghassan; Zhang, Qian; Zucker, Stanley; Cao, Jian

doi:10.2174/1568009616666160216125634

Cited by 28 publications

(22 citation statements)

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“…This conclusion is further supported by the identification of ERG + SMA + cells with active SMAD2 signaling pathway within the infarction and by the results obtained in in vitro experiments. Our findings are in line with the role of MT1-MMP as an activator of epithelial to mesenchymal transition (EMT) in other pathophysiological contexts such as development, cancer, and lung fibrosis (Garmon et al, 2018;Nguyen et al, 2016;Xiong et al, 2017). Interestingly, a recent scRNAseq study carried out on healthy and post-infarcted hearts identified a subset of post-MI Mφs with a HIF1α-dependent signature, which specifically upregulated Mmp14 expression (Dick et al, 2019).…”

Section: Mφ-derived Mt1-mmp Induces Endmt After MIsupporting

confidence: 86%

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

Alonso-Herranz

Sahún-Español

Gonzalo

et al. 2020

Preprint

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Macrophages produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. In this study, we demonstrated that cardiac macrophages increased expression of Mmp14 (MT1-MMP) 7 days post-MI. Specific macrophage-targeting of MT1-MMP (MT1-MMPΔLysM mice) attenuates post-MI cardiac dysfunction, reduces fibrosis, and preserves the cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in macrophages, leading to paracrine SMAD2-mediated signaling in endothelial cells and endothelial-to-mesenchymal transition (EndMT). Post-MI MT1-MMPΔLysM hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and MT1-MMP-deficient macrophages showed a reduced ability to induce EndMT in co-cultures with endothelial cells. Our results demonstrate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify macrophage MT1-MMP as a key regulator of this process. The identified mechanism has potential as a therapeutic target in ischemic heart disease.

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Section: Mφ-derived Mt1-mmp Induces Endmt After MIsupporting

confidence: 86%

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

Alonso-Herranz

Sahún-Español

Gonzalo

et al. 2020

Preprint

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“…ECM proteins stimulate integrin receptors on the membrane of cancer cells, promoting EMT during breast cancer cell invasion, interestingly, by controlling the release of the active TGFβ ligand [ 30 ]. In prostate cancer cells, ECM-deposited latent TGFβ can be activated by membrane type I-matrix metalloprotease (MT1-MMP/MMP14), which then induces the secretion of Wnt5a; the sequential action of TGFβ and Wnt5a sustain EMT and invasiveness of the tumor cells [ 31 ]. Not only glycoproteins, but also glycosaminoglycans, such as hyaluronan, can be induced by TGFβ signaling ( Figure 2 ).…”

Section: Regulation Of Emt By Tgf-βmentioning

confidence: 99%

Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor β

Tsubakihara

Moustakas

2018

IJMS

135

116

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Metastasis of tumor cells from primary sites of malignancy to neighboring stromal tissue or distant localities entails in several instances, but not in every case, the epithelial-mesenchymal transition (EMT). EMT weakens the strong adhesion forces between differentiated epithelial cells so that carcinoma cells can achieve solitary or collective motility, which makes the EMT an intuitive mechanism for the initiation of tumor metastasis. EMT initiates after primary oncogenic events lead to secondary secretion of cytokines. The interaction between tumor-secreted cytokines and oncogenic stimuli facilitates EMT progression. A classic case of this mechanism is the cooperation between oncogenic Ras and the transforming growth factor β (TGFβ). The power of TGFβ to mediate EMT during metastasis depends on versatile signaling crosstalk and on the regulation of successive waves of expression of many other cytokines and the progressive remodeling of the extracellular matrix that facilitates motility through basement membranes. Since metastasis involves many organs in the body, whereas EMT affects carcinoma cell differentiation locally, it has frequently been debated whether EMT truly contributes to metastasis. Despite controversies, studies of circulating tumor cells, studies of acquired chemoresistance by metastatic cells, and several (but not all) metastatic animal models, support a link between EMT and metastasis, with TGFβ, often being a common denominator in this link. This article aims at discussing mechanistic cases where TGFβ signaling and EMT facilitate tumor cell dissemination.

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“…Similar to the point we will discuss later about the reciprocal roles of TGFβ and other cytokines, ECM components such as fibronectin and MMPs are not only induced by TGFβ signaling in mammary epithelial cells, but can themselves provide critical signals that promote the EMT, including control of the activation of TGFβ ligand in the extracellular environment [ 23 ]. The membrane type I-matrix metalloprotease (MT1-MMP or MMP14) promotes EMT and invasiveness by activating extracellular TGFβ, which then induces the secretion of Wnt5a and thus provides a paracrine signal to epithelial prostate cancer cells [ 24 ]. A similar action can be observed for the extracellular glycosaminoglycan hyaluronan, whose synthesis can be induced by TGFβ signaling; hyaluronan activates TGFβ signaling and its downstream transcriptional mediators Snail1 and Twist1, thus promoting EMT and the enrichment of tumor cells in cancer stem cell populations [ 25 ].…”

Section: The Cellular Basis Of Emtmentioning

confidence: 99%

Mechanisms of TGFβ-Induced Epithelial–Mesenchymal Transition

Moustakas

Heldin

2016

JCM

224

162

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Transitory phenotypic changes such as the epithelial–mesenchymal transition (EMT) help embryonic cells to generate migratory descendants that populate new sites and establish the distinct tissues in the developing embryo. The mesenchymal descendants of diverse epithelia also participate in the wound healing response of adult tissues, and facilitate the progression of cancer. EMT can be induced by several extracellular cues in the microenvironment of a given epithelial tissue. One such cue, transforming growth factor β (TGFβ), prominently induces EMT via a group of specific transcription factors. The potency of TGFβ is partly based on its ability to perform two parallel molecular functions, i.e. to induce the expression of growth factors, cytokines and chemokines, which sequentially and in a complementary manner help to establish and maintain the EMT, and to mediate signaling crosstalk with other developmental signaling pathways, thus promoting changes in cell differentiation. The molecules that are activated by TGFβ signaling or act as cooperating partners of this pathway are impossible to exhaust within a single coherent and contemporary report. Here, we present selected examples to illustrate the key principles of the circuits that control EMT under the influence of TGFβ.

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MT1-MMP Activation of TGF-? Signaling Enables Intercellular Activation of an Epithelial-mesenchymal Transition Program in Cancer

Cited by 28 publications

References 0 publications

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor β

Mechanisms of TGFβ-Induced Epithelial–Mesenchymal Transition

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