Matrix metalloproteinase-driven epithelial-mesenchymal transition: implications in health and disease

Abstract

Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells, defined by apical-basal polarity and tight intercellular junctions, acquire migratory and invasive properties characteristic of mesenchymal cells. Under normal conditions, EMT directs essential morphogenetic events in embryogenesis and supports tissue repair. When dysregulated, EMT contributes to pathological processes such as organ fibrosis, chronic inflammation, and cancer progression and metastasis. Matrix metalloproteinases (MMPs)-a family of zinc-dependent proteases that degrade structural components of the extracellular matrix-sit at the nexus of this transition by dismantling basement membranes, activating pro-EMT signaling pathways, and cleaving adhesion molecules. When normally regulated, MMPs promote balanced ECM turnover and support the cyclical remodeling necessary for proper development, wound healing, and tissue homeostasis. When abnormally regulated, MMPs drive excessive ECM turnover, thereby promoting EMT-related pathologies, including tumor progression and fibrotic disease. This review provides an integrated overview of the molecular mechanisms by which MMPs both initiate and sustain EMT under physiological and disease conditions. It discusses how MMPs can potentiate EMT through TGF-β and Wnt/β-catenin signaling, disrupt cell-cell junction proteins, and potentiate the action of hypoxia-inducible factors in the tumor microenvironment. It discusses how these pathologic processes remodel tissues during fibrosis, and fuel cancer cell invasion, metastasis, and resistance to therapy. Finally, the review explores emerging therapeutic strategies that selectively target MMPs and EMT, ranging from CRISPR/Cas-mediated interventions to engineered tissue inhibitors of metalloproteinases (TIMPs), and demonstrates how such approaches may suppress pathological EMT without compromising its indispensable roles in normal biology.

Keywords: Cancer metastasis; Epithelial–mesenchymal transition (EMT); Extracellular matrix (ECM) remodeling; Matrix metalloproteinases (MMPs).

Fig. 1

Overview of the three major EMT subtypes—Type 1 (embryogenesis), Type 2 (wound healing), and Type 3 (cancer metastasis)—and how each relies on a dynamic balance between epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET). In Type 1 EMT, shown in the upper panels, epithelial cells in the early embryo undergo EMT during gastrulation to form the three germ layers (ectoderm, mesoderm, endoderm). Further rounds of EMT–MET underlie critical morphogenetic events, such as neural crest cell formation, enabling the development of tissues including craniofacial structures and peripheral nerves. In Type 2 EMT, depicted in the middle panels, epithelial cells participate in wound repair, briefly adopting a mesenchymal phenotype to migrate into the injury site and facilitate inflammation, proliferation, and remodeling. Dysregulation at this stage can promote pathological scarring or fibrosis. Finally, Type 3 EMT (bottom panels) illustrates the metastatic cascade in cancer. Epithelial tumor cells lose cell–cell junctions and apical–basal polarity, acquire invasive properties (EMT), intravasate into the bloodstream as circulating tumor cells (CTCs), and survive hematogenous or lymphatic transit. Upon reaching distant organs, they typically undergo MET to colonize the new microenvironment and form secondary tumors. Ultimately, each subtype of EMT utilizes similar molecular machinery—transcription factors, signaling pathways, and ECM remodeling—but serves distinct biological ends, from normal development and tissue homeostasis to malignant progression and metastasis. (Illustration created with BioRender.com)

Fig. 2

Matrix Metalloproteinases (MMPs) and Their Roles in Human Disease. In cancer, MMPs drive tumor invasion, metastasis, and immune evasion by degrading ECM components and activating growth factors, with MMP-1, MMP-2, MMP-3, MMP-9, and MMP-14 playing key roles. In cardiovascular diseases, MMP-2 and MMP-9 contribute to arterial ECM breakdown, fibrosis, and ventricular remodeling, increasing the risk of aneurysms and rupture. In neurodegenerative disorders, MMP-2, MMP-3, MMP-8, and MMP-9 disrupt the blood–brain barrier, induce neuroinflammation, and facilitate immune cell infiltration, contributing to conditions like Alzheimer’s disease and multiple sclerosis. In lung diseases, MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12, and MMP-13 promote ECM remodeling, fibrosis, and alveolar destruction, leading to COPD and pulmonary fibrosis. MMPs also play a role in diabetes mellitus by degrading pancreatic islet ECM and promoting β-cell apoptosis, impairing insulin production. In gynecological diseases, MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, and MMP-13 contribute to ovarian cancer metastasis, tumor angiogenesis, and endometriosis progression. MMPs further contribute to autoimmune diseases by driving joint cartilage breakdown in rheumatoid arthritis and worsening inflammation. In ophthalmic diseases, they facilitate ECM degradation and neovascularization, leading to conditions such as diabetic retinopathy and age-related macular degeneration. (Illustration created with BioRender.com)

Fig. 3

Principal extracellular stimuli and intracellular pathways that drive epithelial–mesenchymal transition (EMT). Hypoxia, inflammatory cytokines (e.g., IL-6), and growth factors (e.g., TGF-β, EGF) converge on multiple signaling cascades, including RhoA/ROCK, Smad-dependent transcription, Ras/MAPK/ERK, PI3K/Akt, Wnt/β-catenin, Notch, and Sonic Hedgehog (SHH). These pathways coordinate the upregulation of EMT-inducing transcription factors (Zeb, Snail1/2, Slug, Twist), which repress epithelial genes (E-cadherin, Occludin, Claudin) and induce mesenchymal genes (N-cadherin, Vimentin, Fibronectin). The resulting loss of cell–cell junctions, cytoskeletal reorganization, and acquisition of migratory properties enables cells to transition from a polarized epithelial state to an invasive mesenchymal state. Additionally, integrin-mediated signals and NF-κB activation reinforce pro-EMT transcriptional programs, while hypoxia-inducible factor 1α (HIF-1α) further modulates EMT under low-oxygen conditions. Collectively, these interactions establish a dynamic process that can be reversed (MET) under specific conditions, underscoring the plasticity of epithelial and mesenchymal phenotypes in both normal development and disease. (Illustration created with BioRender.com)