Epithelial-to-mesenchymal transition lowers the cholesterol pathway, wich influences colon tumors differentiation

Colorectal cancer (CRC) is the second cause of death worldwide. Up to 70% of CRC patients will metastasize at one point. Understanding the chain of events that lead to metastasis occurrence is urgent to identify new biomarkers of progression or new targets to prevent and delay disease evolution. Epithelial to mesenchymal transition (EMT) is a major program engaged during metastasis. EMT is extremely complex to analyze in situ due to the broad involvement of its transcription factors. We hypothesized that a relevant and dynamic in vitro model of pure cancer cells will reveal a combination of new genes that might further identify signs of EMT in cancer tissues. We treated HT-29 cells grown in 3D with an EMT-inducing factor, but also looked at reverse changes after EMT-inducing factor removal. For each condition, pan-transcriptomic analyses were done. Genes that were both induced upon EMT induction and inhibited upon EMT release (mesenchymal to epithelial transition or MET) were selected. Consistent with our hypothesis, we identified new genes for the EMT-MET programs. These genes were used to build a metagene that, when applied to a large database of transcriptomic data from primary colorectal tumors (n= 2,239), had an independent prognosis value. Finally, we submitted this metagene to CMap and identified drugs that might affect EMT-MET programs. Statins, well-known inhibitors of cholesterol synthesis, were among them and effectively delayed MET in vitro. These data show that cholesterol and EMT pathways are opposite regulators and impact differently tumors differentiation and outcome.