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.

在正常肠道中，胎儿/再生/复苏细胞状态可在炎症刺激下被诱导。这种细胞命运的可塑性亦是当前人类结直肠癌（CRC）研究的热点议题之一。为了解析其潜在机制，我们构建了携带自然选择遗传突变的CRC类器官，并通过调节细胞外基质（ECM）暴露于两种不同的条件。在所测试的突变谱中，当CRC细胞在富含I型胶原蛋白的支架中进行培养并激活YAP时，相较于在富含层粘连蛋白的Matrigel中培养，能够诱导胎儿/再生/复苏状态。YAP转录的促进由AP-1和TEAD依赖性转录的激活以及通过机械转导抑制肠道谱系决定转录实现。表型转换亦与耐药性相关，这或许可以通过靶向YAP调控元件得到解决。通过机械转导的YAP调控机制是CRC治疗的潜在靶点。