Discovery of non-genomic drivers of yap signaling modulating the cell plasticity in CRC tumor lines
In normal intestine, fetal/regenerative/revival cell state can be induced upon inflammation. This plasticity in cell fate is also one of the current topics in human colorectal cancer (CRC). To dissect the underlying mechanisms, we generated human CRC organoids with naturally selected genetic mutation and exposed them to two different conditions by modulating the extracellular matrix (ECM). Among tested mutation profile, fetal/regenerative/revival states were induced following YAP activation when CRC cells were cultured using collagen type I-enriched scaffold compared to when cultured in laminin-enriched Matrigel. YAP transcription was promoted by activation of AP-1 and TEAD-dependent transcription and suppression of intestinal lineage-determining transcription via mechanotransduction. The phenotypic conversion was also involved in chemoresistance, which could be potentially resolved by targeting the underlying the YAP regulatory elements. YAP regulatory mechanism via mechanotransduction is a potential target of CRC treatment.