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.在正常肠道组织中，炎症刺激可诱导产生胎儿样、再生性或复苏性细胞状态。这种细胞命运的可塑性，也是当前人类结直肠癌（colorectal cancer, CRC）领域的研究热点之一。为解析其潜在分子机制，我们构建了携带自然筛选获得的基因突变的人类结直肠癌类器官，并通过调控细胞外基质（extracellular matrix, ECM）将其置于两种不同培养条件中。在测试的突变谱系中，与在层粘连蛋白富集的基质胶中培养相比，当使用I型胶原富集的支架培养结直肠癌细胞时，YAP（Yes-associated protein，即Yes相关蛋白）激活后可诱导产生胎儿样、再生性或复苏性细胞状态。YAP的转录可通过机械转导机制实现调控：通过激活AP-1（Activator Protein 1，即激活蛋白1）与TEAD（TEA domain transcription factor，即TEA结构域转录因子）依赖的转录程序，同时抑制肠道谱系决定性转录，最终增强YAP的转录。这种表型转化还与化疗耐药性相关，而通过靶向YAP的调控元件有望逆转该耐药性。基于机械转导的YAP调控机制，是结直肠癌治疗的潜在靶点。