PDF(Pubmed)
Abstract：
The lethality, chemoresistance and metastatic characteristics of cancers are associated with phenotypically plastic cancer stem cells (CSCs). How the non-cell autonomous signalling pathways and cell-autonomous transcriptional machinery orchestrate the stem cell-like characteristics of CSCs is still poorly understood. Here we use a quantitative proteomic approach for identifying secreted proteins of CSCs in pancreatic cancer. We uncover that the cell-autonomous E2F1/4-pRb/RBL2 axis balances non-cell-autonomous signalling in healthy ductal cells but becomes deregulated upon KRAS mutation. E2F1 and E2F4 induce whereas pRb/RBL2 reduce WNT ligand expression (e.g. WNT7A, WNT7B, WNT10A, WNT4) thereby regulating self-renewal, chemoresistance and invasiveness of CSCs in both PDAC and breast cancer, and fibroblast proliferation. Screening for epigenetic enzymes identifies GCN5 as a regulator of CSCs that deposits H3K9ac onto WNT promoters and enhancers. Collectively, paracrine signalling pathways are controlled by the E2F-GCN5-RB axis in diverse cancers and this could be a therapeutic target for eliminating CSCs.
摘要：
杀伤力，癌症的化学抗性和转移特征与表型可塑性癌症干细胞(CSC)相关。非细胞自主信号通路和细胞自主转录机制如何协调CSC的干细胞样特征仍然知之甚少。在这里，我们使用定量蛋白质组学方法来鉴定胰腺癌中CSC的分泌蛋白。我们发现细胞自主E2F1/4-pRb/RBL2轴平衡健康导管细胞中的非细胞自主信号，但在KRAS突变后变得失调。E2F1和E2F4诱导，而pRb/RBL2减少WNT配体表达（例如WNT7A，WNT7B,WNT10A,WNT4)从而调节自我更新，PDAC和乳腺癌中CSC的化学抗性和侵袭性，和成纤维细胞增殖。表观遗传学酶的筛选将GCN5鉴定为CSC的调节剂,其将H3K9ac沉积到WNT启动子和增强子上。总的来说，在多种癌症中，旁分泌信号通路受E2F-GCN5-RB轴控制，这可能是消除CSC的治疗靶标。
