Cell Cycle-Dependent Tumor Engraftment and Migration Are Enabled by Aurora-A

• Published in: Molecular cancer research 2018-01, Vol.16 (1), p.16-31
• Main Authors: Chu, Tony L H, Connell, Marisa, Zhou, Lixin, He, Zhengcheng, Won, Jennifer, Chen, Helen, Rahavi, Seyed M R, Mohan, Pooja, Nemirovsky, Oksana, Fotovati, Abbas, Pujana, Miguel Angel, Reid, Gregor S D, Nielsen, Torsten O, Pante, Nelly, Maxwell, Christopher A
• Format: Article
• Language: English
• Subjects: Animals; Aurora kinase; Aurora Kinase A - genetics; Aurora Kinase A - metabolism; Breast cancer; Cancer; Cell adhesion & migration; Cell cycle; Cell Cycle Proteins - metabolism; Cell migration; Centrosomes; Cytoskeleton; Epithelial cells; Estrogen receptors; Estrogens; Female; Fluorescence; Humans; Hyaluronic acid; Kinases; Kinetics; Mice; Nuclear transport; Nucleation; Patients; Phenotypes; Protein transport; Substrates; Survival; Transfection; Transport; Tumors; Ubiquitin; Wounds
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.mcr-17-0417

Cell-cycle progression and the acquisition of a migratory phenotype are hallmarks of human carcinoma cells that are perceived as independent processes but may be interconnected by molecular pathways that control microtubule nucleation at centrosomes. Here, cell-cycle progression dramatically impacts the engraftment kinetics of 4T1-luciferase2 breast cancer cells in immunocompetent BALB/c or immunocompromised NOD-SCID gamma (NSG) mice. Multiparameter imaging of wound closure assays was used to track cell-cycle progression, cell migration, and associated phenotypes in epithelial cells or carcinoma cells expressing a fluorescence ubiquitin cell-cycle indicator. Cell migration occurred with an elevated velocity and directionality during the S-G -phase of the cell cycle, and cells in this phase possess front-polarized centrosomes with augmented microtubule nucleation capacity. Inhibition of Aurora kinase-A (AURKA/Aurora-A) dampens these phenotypes without altering cell-cycle progression. During G -phase, the level of phosphorylated Aurora-A at centrosomes is reduced in hyaluronan-mediated motility receptor (HMMR)-silenced cells as is the nuclear transport of TPX2, an Aurora-A-activating protein. TPX2 nuclear transport depends upon HMMR-T703, which releases TPX2 from a complex with importin-α (KPNA2) at the nuclear envelope. Finally, the abundance of phosphorylated HMMR-T703, a substrate for Aurora-A, predicts breast cancer-specific survival and relapse-free survival in patients with estrogen receptor (ER)-negative ( = 941), triple-negative (TNBC) phenotype ( = 538), or basal-like subtype ( = 293) breast cancers, but not in those patients with ER-positive breast cancer ( = 2,218). Together, these data demonstrate an Aurora-A/TPX2/HMMR molecular axis that intersects cell-cycle progression and cell migration. Tumor cell engraftment, migration, and cell-cycle progression share common regulation of the microtubule cytoskeleton through the Aurora-A/TPX2/HMMR axis, which has the potential to influence the survival of patients with ER-negative breast tumors. .