Golgi compaction supports metastasis initiated by epithelial-to-mesenchymal transition
In some tumors, metastasis is accompanied by a shift in tumor cells from epithelial to mesenchymal states. Metastasis is also supported by secretory factors that drive angiogenesis and other pro-metastatic processes. These secretory factors are regulated by the Golgi complex, an organelle that packs, sorts, and transports vesicles to various intracellular locations. Recent work by Jonathan Kurie’s lab at MD Anderson Cancer Center has shown that the epithelial-to-mesenchymal transition (EMT) is accompanied a compaction of Golgi organelles that may enhance pro-metastatic vesicle trafficking. This compaction of Golgi organelles required expression of the scaffolding protein PAQR11. Although previous studies have indicated that Golgi dispersal can mediate pro-metastatic processes, this study found, in contrast, that Golgi compaction driven by PAQR11 was essential for metastasis in mouse models of lung adenocarcinoma. Furthermore, high expression of PAQR11 was correlated with EMT and shorter survival in human cancers. These findings indicate a distinct model for EMT-driven metastasis that is supported by Golgi compaction.
In the accompanying image, confocal micrographs illustrate Golgi elements in murine lung adenocarcinoma cells. In epithelial cells (left images), Golgi organelles (green) are small, numerous, and dispersed throughout the cytoplasm. In contrast, Golgi organelles in mesenchymal cells (middle, top) and EMT-driven epithelial cells (middle, bottom) appear more concentrated. The rightmost image displays mesenchymal cells (DAPI, blue) with compacted Golgi complex (white) in a wound healing assay.
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Abstract
Tumor cells gain metastatic capacity through a Golgi phosphoprotein 3–dependent (GOLPH3-dependent) Golgi membrane dispersal process that drives the budding and transport of secretory vesicles. Whether Golgi dispersal underlies the pro-metastatic vesicular trafficking that is associated with epithelial-to-mesenchymal transition (EMT) remains unclear. Here, we have shown that, rather than causing Golgi dispersal, EMT led to the formation of compact Golgi organelles with improved ribbon linking and cisternal stacking. Ectopic expression of the EMT-activating transcription factor ZEB1 stimulated Golgi compaction and relieved microRNA-mediated repression of the Golgi scaffolding protein PAQR11. Depletion of PAQR11 dispersed Golgi organelles and impaired anterograde vesicle transport to the plasma membrane as well as retrograde vesicle tethering to the Golgi. The N-terminal scaffolding domain of PAQR11 was associated with key regulators of Golgi compaction and vesicle transport in pull-down assays and was required to reconstitute Golgi compaction in PAQR11-deficient tumor cells. Finally, high PAQR11 levels were correlated with EMT and shorter survival in human cancers, and PAQR11 was found to be essential for tumor cell migration and metastasis in EMT-driven lung adenocarcinoma models. We conclude that EMT initiates a PAQR11-mediated Golgi compaction process that drives metastasis.
Authors
Xiaochao Tan, Priyam Banerjee, Hou-Fu Guo, Stephen Ireland, Daniela Pankova, Young-ho Ahn, Irodotos Michail Nikolaidis, Xin Liu, Yanbin Zhao, Yongming Xue, Alan R. Burns, Jonathon Roybal, Don L. Gibbons, Tomasz Zal, Chad J. Creighton, Daniel Ungar, Yanzhuang Wang, Jonathan M. Kurie
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ISSN: 0021-9738 (print), 1558-8238 (online)