Our goal is to better understand the biologic basis for metastasis of KRAS-mutant lung cancer (KMLC) and to develop novel therapeutic approaches on the basis of that improved understanding. Progress in this area could potentially have a tremendous public health impact because metastasis is the primary cause of death from lung cancer, and there are currently few effective therapeutic options for KMLC. Towards that goal, we generated KP mice, which develop metastatic lung adenocarcinoma owing to the co-expression of K-rasG12D and p53R172H. Our preliminary results show that Zeb1, a transcriptional driver of metastasis in KP mice and predictor of poor clinical outcome in multiple epithelial tumor types, caused the Golgi organelle to become more compact and centralized, form ribbon-linked cisternal stacks, and stimulate vesicle trafficking in the anterograde direction. ZEB1 increased the expression of PAQR11, a Golgi scaffolding protein that was required for ZEB1-induced Golgi organelle integrity and tumor cell metastatic properties. In pull-down assays, the scaffolding domain of PAQR11 bound to vesicle coatomer proteins, GTPases that regulate vesicle budding and tethering, and dynein motor proteins that transport cargo along microtubules towards the cell's center. PAQR11 depletion reduced the migratory, invasive, and metastatic activities of lung adenocarcinoma cells derived from KP mice and human KMLC cells. High intra-tumoral PAQR11 levels predicted shorter survival in a compendium of 11 independent human lung cancer cohorts and a pan-cancer analysis of over 30 tumor types. On the basis of our preliminary results, we hypothesize that KMLCs gain metastatic potential through transcriptional control of the Golgi apparatus. To test this hypothesis, we propose two Specific Aims. In the first Aim, we will determine whether PAQR11 facilitates the dynein-mediated transport of Golgi mini-stacks and ribbon-linking and stacking of cisternae to create a centralized Golgi complex that drives anterograde vesicle trafficking and promotes tumor cell motility. In the second Aim, we will determine the extent to which ectopic PAQR11 expression promotes the metastasis of spontaneously occurring KMLCs. If our hypothesis is correct, these findings will advance our understanding of the mechanisms by which KMLC cells gain metastatic propensity and provide researchers in the field with new tools to investigate Golgi dynamics in tumor cells in the native microenvironment of the lung, an improved understanding of the underlying causes of lung adenocarcinoma metastasis, and a basis for investigating agents that target mediators of Zeb1 in clinical trials to prevent KMLC metastasis.

Public Health Relevance

There are few effective therapeutic options for patients with metastatic KRAS-mutant lung adenocarcinoma, and there is an urgent need to develop a better understanding of the biological basis of metastasis that will lead to the identification of rational therapeutic targets for patients with KRAS-mutant lung adenocarcinoma. On the basis of the preliminary results presented here, we postulate that KRAS-mutant lung adenocarcinoma cells gain metastatic ability by increasing the expression of a protein that enhances the structural integrity of the Golgi apparatus, an organelle that controls the motility and invasiveness of tumor cells. If proven true, these findings would advance our understanding of the mechanisms by which KRAS-mutant lung adenocarcinoma cells metastasize and would provide a rationale for the discovery of agents that target the Golgi to prevent metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Ault, Grace S
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University of Texas MD Anderson Cancer Center
Internal Medicine/Medicine
United States
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Tan, Xiaochao; Banerjee, Priyam; Liu, Xin et al. (2018) The epithelial-to-mesenchymal transition activator ZEB1 initiates a prometastatic competing endogenous RNA network. J Clin Invest 128:1267-1282
Tan, Xiaochao; Banerjee, Priyam; Guo, Hou-Fu et al. (2017) Epithelial-to-mesenchymal transition drives a pro-metastatic Golgi compaction process through scaffolding protein PAQR11. J Clin Invest 127:117-131