Attenuated Chromosome Oscillation as a Cause of Chromosomal Instability in Cancer Cells

Chromosomal instability (CIN) is commonly seen in cancer cells, and related to tumor progression and poor prognosis. Among the causes of CIN, insufficient correction of erroneous kinetochore (KT)-microtubule (MT) attachments plays pivotal roles in various situations. In this review, we focused on the previously unappreciated role of chromosome oscillation in the correction of erroneous KT-MT attachments, and its relevance to the etiology of CIN. First, we provided an overview of the error correction mechanisms for KT-MT attachments, especially the role of Aurora kinases in error correction by phosphorylating Hec1, which connects MT to KT. Next, we explained chromosome oscillation and its underlying mechanisms. Then we introduced how chromosome oscillation is involved in the error correction of KT-MT attachments, based on recent findings. Chromosome oscillation has been shown to promote Hec1 phosphorylation by Aurora A which localizes to the spindle. Finally, we discussed the link between attenuated chromosome oscillation and CIN in cancer cells. This link underscores the role of chromosome dynamics in mitotic fidelity, and the mutual relationship between defective chromosome dynamics and CIN in cancer cells that can be a target for cancer therapy.

Use of cell doublets for studying cytokinesis regulation reveals a new form of cytokinesis regression

Cytokinesis mediates separation of daughter cells at the end of cell division. We have developed a high-throughput approach for monitoring cell-autonomous cytokinesis in non-adherent cells. Focusing on cytokinesis termination, we show that chemical inhibition of protein phosphatase 1 (PP1) and PP2A specifically in late cytokinesis activates cytokinesis regression, which is distinct from any known cytokinesis failure, and is not a by-product of abnormal furrow ingression or chromatin bridges. This process is characterized by the formation of cortical blebs primarily at the intercellular bridge, reopening of the cleavage furrow and reassembly of an interphase-like microtubule network, but not by chromatin recondensation and mitotic spindle formation. Finally, cytokinesis regression is suppressed by chemical inhibition of aurora kinases but not Cdk1 or PLK1. Altogether, our results highlight a hitherto uncharacterized facet of the counter-activity of PP1/PP2A and aurora kinases in the final step of cell division, which ultimately secure the conclusion of cytokinesis, thereby preventing polyploidy and genomic instability.

The Relevance of Aurora Kinase Inhibition in Hematological Malignancies

Aurora kinases are a family of serine/threonine protein kinases that play a central role in eukaryotic cell division. Overexpression of aurora kinases in cancer and their role as major regulators of the cell cycle quickly inspired the idea that their inhibition might be a potential pathway when treating oncologic patients. Over the past couple of decades, the search for designing and testing of molecules capable of inhibiting aurora activities fueled many pre-clinical and clinical studies. In this study, data from the past 10 years of in vitro and in vivo investigations, as well as clinical trials, utilizing aurora kinase inhibitors as therapeutics for hematological malignancies were compiled and discussed, aiming to highlight potential uses of these inhibitors as a novel monotherapy model or alongside conventional chemotherapies. While there is still much to be elucidated, it is clear that these kinases play a key role in oncogenesis, and their manageable toxicity and potentially synergistic effects still render them a focus of interest for future investigations in combinatorial clinical trials

Adhesion-growth factor crosstalk regulates AURKB activation and ERK signaling in re-adherent fibroblasts

Aurora kinases despite their similarity have distinct roles in the cell cycle, which is regulated by cell-matrix adhesion and growth factors. This study reveals loss of adhesion and re-adhesion to differentially regulate Aurora kinases. AURKB activation that drops on the loss of adhesion recovers on re-adhesion in serum-deprived conditions but not in the presence of serum growth factors. A rapid 30min serum treatment of serum-deprived cells blocks the adhesion-dependent recovery of AURKB, which negatively corelates with Erk activation. AZD mediated inhibition of AURKB in serum-deprived re-adherent cells promotes Erk activation and membrane ruffling, comparable to presence of serum. These studies thus define a novel adhesion-growth factor-dependent regulation of AURKB that controls adhesion-dependent Erk activation in re-adherent fibroblasts.

High-throughput kinase inhibitor screening reveals roles for Aurora and Nuak kinases in neurite initiation and dendritic branching

Kinases are essential regulators of a variety of cellular signaling processes, including neurite formation—a foundational step in neurodevelopment. Aberrant axonal sprouting and failed regeneration of injured axons are associated with conditions like traumatic injury, neurodegenerative disease, and seizures. Investigating the mechanisms underlying neurite formation will allow for identification of potential therapeutics. We used a kinase inhibitor library to screen 493 kinase inhibitors and observed that 45% impacted neuritogenesis in Neuro2a (N-2a) cells. Based on the screening, we further investigated the roles of Aurora kinases A, B, and C and Nuak kinases 1 and 2. The roles of Aurora and Nuak kinases have not been thoroughly studied in the nervous system. Inhibition or overexpression of Aurora and Nuak kinases in primary cortical neurons resulted in various neuromorphological defects, with Aurora A regulating neurite initiation, Aurora B and C regulating neurite initiation and elongation, all Aurora kinases regulating arborization, and all Nuak kinases regulating neurite initiation and elongation and arborization. Our high-throughput screening and analysis of Aurora and Nuak kinases revealed their functions and may contribute to the identification of therapeutics.

Integrative Network Analysis of Early-Stage Lung Adenocarcinoma Identifies Aurora Kinase Inhibition as Interceptor of Invasion and Progression

We present a gene signature distinguishing invasive and indolent tumors among early-stage lung adenocarcinoma (esLUAD). An Invasiveness Score estimated using the gene signature was strongly associated with survival of esLUAD patients in multiple independent cohorts and with the invasiveness phenotype in lung cancer cell lines. Regulatory network analysis identified aurora kinase as one of master regulators of the gene signature and perturbation of aurora kinases in vitro and in vivo reduced tumor invasion. Our study suggests aurora kinases as a novel target for treating early-stage invasive lung adenocarcinoma.

Differential reprogramming of breast cancer subtypes in 3D cultures and implications for sensitivity to targeted therapy

Screening for effective candidate drugs for breast cancer has shifted from two-dimensional (2D) to three-dimensional (3D) cultures. Here we systematically compared the transcriptomes of these different culture conditions by RNAseq of 14 BC cell lines cultured in both 2D and 3D conditions. All 3D BC cell cultures demonstrated increased mitochondrial metabolism and downregulated cell cycle programs. Luminal BC cells in 3D demonstrated overall limited reprogramming. 3D basal B BC cells showed increased expression of extracellular matrix (ECM) interaction genes, which coincides with an invasive phenotype not observed in other BC cells. Genes downregulated in 3D were associated with metastatic disease progression in BC patients, including cyclin dependent kinases and aurora kinases. Furthermore, the overall correlation of the cell line transcriptome to the BC patient transcriptome was increased in 3D cultures for all TNBC cell lines. To define the most optimal culture conditions to study the oncogenic pathway of interest, an open source bioinformatics strategy was established.