Metastasis, cancer spreading, is often a final and fatal stage in the progression of solid malignancies. Early detection of localized breast cancer results in a higher relative five-year survival rate (98%) while the relative five-year survival rae drops significantly (26%) for those women who have distant metastases. Therefore, a better understanding of mechanistic insight regarding the development and progression of this disease is of extreme importance in clinical setting. Our study revealed that cytokine CCL18 released from tumor-associated macrophage promotes breast cancer metastasis and serves as a novel indicator for poor survival in the clinical oncology (Chen et al., 2011. Cancer Cell). In addition, our recent study identified a breast cancer metastasis signaling network involving CCL18 and its potential effectors ARF6-ACAP4-ezrin. However, little is known regarding the molecular mechanism(s) by which CCL18 operates in breast cancer metastasis. The long-term goal of our research is to delineate how ARF6-ACAP4-ezrin interaction orchestrates stimulus-coupled breast cancer metastasis. To address this question, three Specific Aims are proposed: first, we will delineate the ARF6 activity gradient underlying breast cancer cell dynamics using a novel biosensor combined with ACAP4 small molecule inhibitors;second, we evaluate how phospho-ezrin interacts with ACAP4 using epitope-tagging, chemical foot-printing, and cross-linking approaches. These studies will involve a detailed analysis of the structural determinants that mediate a direct ezrin-ACAP4 contact. Binding domain data will be used to design peptides that potently and specifically perturb ezrin-ACAP4 interactions in in vitro binding assays. The importance of such an interaction in breast cancer invasion will then be evaluated by functional assay and supra-resolution imaging analysis. Third, we plan to investigate the potential mechanisms underlying ACAP4-mediated breast cancer interacts in animals. These studies will be facilitated by in vivo bioluminescence images coupled with small molecule inhibitor treatment in live xenografted animals. Studying the molecular mechanisms underlying breast cancer metastasis is of great significance in understanding the solid tumor progression, and is also expected to be of great benefit in leading to pharmacological strategies for preventing tumor cell spreading.
The proposed line of investigations represents a highly integrated translational effort to delineate breast tumor metastasis and provide a strategy for disease intervention.
|Yuan, Xiao; Yao, Phil Y; Jiang, Jiying et al. (2017) MST4 kinase phosphorylates ACAP4 protein to orchestrate apical membrane remodeling during gastric acid secretion. J Biol Chem 292:16174-16187|
|Mo, Fei; Zhuang, Xiaoxuan; Liu, Xing et al. (2016) Acetylation of Aurora B by TIP60 ensures accurate chromosomal segregation. Nat Chem Biol 12:226-32|
|Qin, Bo; Cao, Dan; Wu, Huihui et al. (2016) Phosphorylation of SKAP by GSK3? ensures chromosome segregation by a temporal inhibition of Kif2b activity. Sci Rep 6:38791|
|Duan, Hequan; Wang, Chunli; Wang, Ming et al. (2016) Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation. J Biol Chem 291:21123-21136|
|Jiang, Hao; Wang, Wenwen; Zhang, Yin et al. (2015) Cell Polarity Kinase MST4 Cooperates with cAMP-dependent Kinase to Orchestrate Histamine-stimulated Acid Secretion in Gastric Parietal Cells. J Biol Chem 290:28272-85|
|Cao, Dan; Su, Zeqi; Wang, Wenwen et al. (2015) Signaling Scaffold Protein IQGAP1 Interacts with Microtubule Plus-end Tracking Protein SKAP and Links Dynamic Microtubule Plus-end to Steer Cell Migration. J Biol Chem 290:23766-80|
|Shao, Hengyi; Huang, Yuejia; Zhang, Liangyu et al. (2015) Spatiotemporal dynamics of Aurora B-PLK1-MCAK signaling axis orchestrates kinetochore bi-orientation and faithful chromosome segregation. Sci Rep 5:12204|
|Zhu, Lijuan; Wang, Zhikai; Wang, Wenwen et al. (2015) Mitotic Protein CSPP1 Interacts with CENP-H Protein to Coordinate Accurate Chromosome Oscillation in Mitosis. J Biol Chem 290:27053-66|
|Yan, Maomao; Chu, Lingluo; Qin, Bo et al. (2015) Regulation of NDR1 activity by PLK1 ensures proper spindle orientation in mitosis. Sci Rep 5:10449|
|Liu, Xing; Song, Zhenwei; Huo, Yuda et al. (2014) Chromatin protein HP1 interacts with the mitotic regulator borealin protein and specifies the centromere localization of the chromosomal passenger complex. J Biol Chem 289:20638-49|
Showing the most recent 10 out of 30 publications