Abstract
Epithelial-to-mesenchymal transition (EMT) is a transcriptionally governed process by which cancer cells establish a front-rear polarity axis that facilitates motility and invasion. Dynamic assembly of focal adhesions and other actin-based cytoskeletal structures on the leading edge of motile cells requires precise spatial and temporal control of protein trafficking. Yet, the way in which EMT-activating transcriptional programs interface with vesicular trafficking networks that effect cell polarity change remains unclear. Here, by utilizing multiple approaches to assess vesicular transport dynamics through endocytic recycling and retrograde trafficking pathways in lung adenocarcinoma cells at distinct positions on the EMT spectrum, we find that the EMT-activating transcription factor ZEB1 accelerates endocytosis and intracellular trafficking of plasma membrane-bound proteins. ZEB1 drives turnover of the MET receptor tyrosine kinase by hastening receptor endocytosis and transport to the lysosomal compartment for degradation. ZEB1 relieves a plus-end-directed microtubule-dependent kinesin motor protein (KIF13A) and a clathrin-associated adaptor protein complex subunit (AP1S2) from microRNA-dependent silencing, thereby accelerating cargo transport through the endocytic recycling and retrograde vesicular pathways, respectively. Depletion of KIF13A or AP1S2 mitigates ZEB1-dependent focal adhesion dynamics, front-rear axis polarization, and cancer cell motility. Thus, ZEB1-dependent transcriptional networks govern vesicular trafficking dynamics to effect cell polarity change.
Highlights
Epithelial-to-mesenchymal transition (EMT) is a transcriptionally governed process by which cancer cells establish a front-rear polarity axis that facilitates motility and invasion
We tested this hypothesis in murine and human lung adenocarcinoma (LUAD) cell lines at distinct positions on the EMT spectrum; LUAD cells classified as “epithelial” have uniformly epithelial gene expression patterns and exhibit low metastatic propensities, whereas those classified as “mesenchymal” exhibit partial EMT features characterized by bi-phenotypic gene expression patterns, a capacity to undergo EMT or the reverse process in response to extracellular cues, and an aggressive metastatic propensity driven by high levels of the EMTactivating transcription factor ZEB12,15–17
We show that ZEB1 influences the intracellular fate of a receptor tyrosine kinase that undergoes endocytosis following ligand-binding and identify a ZEB1-dependent transcriptional program that accelerates vesicular trafficking through the endocytic recycling and retrograde pathways and thereby facilitates the establishment of a front-rear polarity axis
Summary
Epithelial-to-mesenchymal transition (EMT) is a transcriptionally governed process by which cancer cells establish a front-rear polarity axis that facilitates motility and invasion. We postulated that EMT-activating transcription factors control endocytic vesicular trafficking networks to establish a front-rear polarity axis that facilitates motility We tested this hypothesis in murine and human lung adenocarcinoma (LUAD) cell lines at distinct positions on the EMT spectrum; LUAD cells classified as “epithelial” have uniformly epithelial gene expression patterns and exhibit low metastatic propensities, whereas those classified as “mesenchymal” exhibit partial EMT features characterized by bi-phenotypic gene expression patterns (e.g., high CDH1, CDH2, and VIM), a capacity to undergo EMT or the reverse process in response to extracellular cues, and an aggressive metastatic propensity driven by high levels of the EMTactivating transcription factor ZEB12,15–17. ZEB1 influences vesicular trafficking dynamics to execute cell polarity change
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