While lengthening of the cell cycle and G1 phase is a generic feature of tissue maturation during development, the underlying mechanism remains still poorly understood. Here we develop a time lapse imaging strategy to measure the four cell cycle phases in single neural progenitor cells in their endogenous environment. We show that neural progenitors are widely heterogeneous regarding the cell cycle length. This duration variability is distributed over all phases of the cell cycle, with the G1 phase being the one contributing the most. Within one cell cycle, each phase duration appears stochastic and independent except for a correlation between S and M phase duration. Lineage analysis indicates that the majority of daughter cells may have longer G1 phase than mother cells suggesting that at each cell cycle a mechanism lengthens the G1 phase. We identify that the CDC25B phosphatase known to regulate G2/M transition, indirectly increases the duration of the G1 phase partly through delaying restriction point crossing. We propose that CDC25B increases G1 phase range of heterogeneity revealing a novel mechanism of G1 lengthening associated with tissue development.
Characterization of the molecular mechanisms involved in tumor cell clustering could open the way to new therapeutic strategies. Towards this aim, we used an in vitro quantitative procedure to monitor the anchorage-independent cell aggregation kinetics in a panel of 25 cancer cell lines. The analysis of the relationship between selected aggregation dynamic parameters and the gene expression data for these cell lines from the CCLE database allowed identifying genes with expression significantly associated with aggregation parameter variations. Comparison of these transcripts with the perturbagen signatures from the Connectivity Map resource highlighted that they were strongly correlated with the transcriptional signature of most histone deacetylase (HDAC) inhibitors. Experimental evaluation of two HDAC inhibitors (SAHA and ISOX) showed that they inhibited the initial step of in vitro tumor cell aggregation. This validates our findings and reinforces the potential interest of HDCA inhibitors to prevent metastasis spreading.
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