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Updated: Mar 25, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
MT1-MMP Activation of TGF-β Signaling Enables Intercellular Activation of an Epithelial-mesenchymal Transition
Hoang-Lan Nguyen, Pournima Kadam, Alex Helkin
1Department of Medicine, Stony Brook University, Stony Brook, NY 11794. Jian.Cao@stonybrookmedicine.edu.
Abstract:
Membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) is associated with cancer invasion and metastasis leading to poor patient prognosis. MT1-MMP mediates cancer cell invasion via degradation of basement membrane and extracellular matrix, and induction of cell migration. However, MT1-MMP expression in the cancer stroma can drive invasion of carcinoma cells in vivo, suggesting MT1-MMP may also promote cancer invasiveness via paracrinemediated mechanisms. A major step in cancer cell metastasis is thought to be an epithelial-mesenchymal transition (EMT), in which carcinoma cells evolve from a stationary epithelial phenotype to a more motile mesenchymal phenotype. We demonstrate here that EMT is triggered by MT1-MMP-mediated activation of TGF-. signaling, involving induction of CUTL1 and subsequently, of Wnt5a. Mesenchymal-like cancer cells expressing endogenous MT1-MMP reverted to an epithelial phenotype when MT1-MMP, SMAD4, CUTL1, or Wnt5a expression or TGF-. activity was inhibited. Wnt5a knockdown in MT1- MMP expressing LNCaP cells caused decreased cell migration and cell growth in soft agar. While MT1-MMP expression did not affect total TGF-. level, MT1-MMP catalytic activity increased the availability of active TGF-., enabling MT1-MMP-expressing cells to activate the EMT in nearby cells. MT1-MMP-expressing cells induced co-cultured non-MT1-MMP-expressing cells to undergo EMT by a TGF-.-dependent process. These results highlight a pathway by which tumor invasiveness may be expanded via MT1-MMP-mediated activation of TGF-. signaling, enabling autocrine and paracrine-mediated induction of EMT.
Insights
Membrane type 1-matrix metalloproteinase (MT1-MMP) activates TGF-β signaling, triggering epithelial-mesenchymal transition (EMT) and promoting cancer cell invasion and metastasis through autocrine and paracrine mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Membrane type 1-matrix metalloproteinase (MT1-MMP) is linked to cancer invasion and metastasis, negatively impacting patient prognosis.
- MT1-MMP facilitates cancer cell invasion by degrading the extracellular matrix and promoting cell migration.
- Stromal MT1-MMP expression can drive carcinoma cell invasion, suggesting paracrine roles in invasiveness.
Purpose of the Study:
- To investigate the role of MT1-MMP in initiating epithelial-mesenchymal transition (EMT), a key process in cancer metastasis.
- To elucidate the molecular pathways linking MT1-MMP to EMT induction, including the involvement of TGF-β signaling, CUTL1, and Wnt5a.
- To determine whether MT1-MMP can induce EMT in adjacent cancer cells via paracrine signaling.
Main Methods:
- Investigated the role of MT1-MMP in EMT induction through TGF-β signaling, CUTL1, and Wnt5a.
- Utilized gene silencing (knockdown) of MT1-MMP, SMAD4, CUTL1, and Wnt5a to assess their impact on EMT.
- Assessed cell migration and anchorage-independent growth (soft agar assay) in response to Wnt5a knockdown.
- Examined the effect of MT1-MMP on active TGF-β availability and its role in inducing EMT in co-cultured cells.
Main Results:
- MT1-MMP triggers EMT by activating TGF-β signaling, leading to the induction of CUTL1 and Wnt5a.
- Inhibition of MT1-MMP, SMAD4, CUTL1, or Wnt5a, or TGF-β activity, reversed EMT in mesenchymal-like cancer cells.
- Wnt5a knockdown in MT1-MMP-expressing cells reduced cell migration and soft agar growth.
- MT1-MMP catalytic activity increased active TGF-β, enabling autocrine and paracrine EMT induction in neighboring cells.
Conclusions:
- MT1-MMP-mediated activation of TGF-β signaling is a critical pathway for inducing EMT in cancer cells.
- MT1-MMP promotes cancer cell invasion and metastasis through both autocrine and paracrine induction of EMT.
- Targeting MT1-MMP or its downstream signaling pathways (TGF-β, CUTL1, Wnt5a) may offer therapeutic strategies against cancer spread.
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Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...