Highlights of This Issue

Abstract

Glioblastoma, despite its low incidence, is a fairly common and aggressive primary brain tumor. Glioma-initiating cells (GIC) are a subset of tumor cells characterized by their self-renewal ability and tumorigenicity and have been linked to progression, recurrence, and therapy resistance. Therefore, an understanding of the molecular mechanisms that govern GIC self-renewal is critical for the development of more effective therapies. Xi and colleagues reveal that Aurora Kinase A (AURKA) regulates GIC self-renewal capacity and tumorigenicity by stabilizing β-catenin. Mechanistically, AURKA interacts directly with AXIN and stabilizes β-catenin, in part by sequestering AXIN from the β-catenin destruction complex. Stable knockdown of AURKA increased phospho-β-catenin bound to AXIN, which was rescued by the AURKA kinase dead mutant D274A, which lacks the ability to phosphorylate GSK3β. These findings implicate AURKA as a novel molecular target for glioblastoma treatment strategies.Many cancer therapeutics exert cell-killing effects in a cell cycle–dependent manner; however, coordination between metabolic systems and the different phases of the cell cycle is poorly understood. A more thorough understanding of energy metabolism from a cell cycle perspective will likely provide unique opportunities to enhance therapeutic efficacy. To this end, Bao and colleagues coupled cell-cycle phase-dependent, fluorescent labeling and microscopic imaging mass spectrometry to quantify phase-specific metabolites in individual cancer cells in a metastatic tumor model. Critically, cancer cells in G1-phase are dependent on glycolysis, whereas those in G2–M phase are more oxidative in order to maintain ATP. This study highlights the importance of energy management as a function of cell-cycle progression and suggests that cell cycle–specific metabolic pathways are viable targets for anticancer treatments.Recent evidence suggests that a subset of protein phosphatase 2A (PP2A) holoenzymes comprised of the regulatory subunit B56, in particular B56γ-PP2A, function as tumor suppressors. However, the underlying mechanism(s) for B56γ-PP2A inactivation in cancer have not been systematically evaluated. Nobumori and colleagues characterized a panel of B56γ mutations identified in human clinical specimens and cancer cell lines. Importantly, the study determined that the mutations lost B56γ tumor-suppressive activity by two distinct means: one mechanism by disrupting interactions with the PP2A regulatory A/catalytic C (AC core) and the other mechanism with B56γ–PP2A substrates (including p53). Overall, these results provide new mechanistic insight for the inactivation of tumor-suppressive functions of B56γ-PP2A and further indicate the importance of B56γ-PP2A in tumor suppression.The forkhead family transcription factor, FOXQ1, is one of the most consistently reported upregulated genes in colorectal cancer. Moreover, it was discovered to be upregulated in both epithelial and stromal resected tissue compartments, suggesting that it has important biologic activities. Abba and colleagues evaluated several colorectal cell lines to determine the endogenous expression of FOXQ1. Through overexpression and silencing studies it was revealed that FOXQ1 significantly affects migration, invasion, and distant metastasis with minimal effects on tumor growth. Gene expression analyses using resected patient tissue identified a strong correlation between FOXQ1 and Twist1. Upon further mechanistic study, Twist1 and E-cadherin were shown to be critical mediators of these metastatic events. Thus, targeting FOXQ1 and/or its downstream effectors could mitigate colorectal cancer metastasis.