Quantitative Analysis of Cell Aggregation Dynamics Identifies HDAC Inhibitors as Potential Regulators of Cancer Cell Clustering

Simple SummaryMetastases formation involves the formation, circulation and seeding of cohesive group of tumor cells called circulating tumors cells clusters at distant organs from the primary tumor. These clusters have a much higher metastatic potential than individual circulating tumor cell, it is therefore important to understand the molecular mechanisms involved in their formation. To this aim, in this study, from the analysis of the relationship between in vitro aggregation quantitative characterization of 25 cancer cell lines and their expression data, we identified genes significantly associated with aggregation. Interestingly, we found that these genes were strongly correlated with the transcriptional signature induced by HDAC inhibitors treatment and we finally showed experimentally that two HDAC inhibitors inhibits tumor cells cluster formation in vitro. These results open new therapeutic perspectives to prevent metastasis formation.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.

Automated summary

This study identified genes significantly associated with tumor cell aggregation by analyzing the relationship between aggregation quantitative characterization of 25 cancer cell lines and their expression data. Interestingly, these genes were found to be strongly correlated with the transcriptional signature induced by HDAC inhibitors treatment, and experimental evidence showed that two HDAC inhibitors could inhibit tumor cell cluster formation in vitro. These findings open up new therapeutic perspectives for preventing metastasis formation.