Chang Chao-Hui, Liu Feng, Militi Stefania, Hester Svenja, Nibhani Reshma, Deng Siwei, Dunford James, Rendek Aniko, Soonawalla Zahir, Fischer Roman, Oppermann Udo, Pauklin Siim
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, OX3 7LD, UK.
Target Discovery Institute, Nuffield Department of Medicine, Old Road, University of Oxford, Oxford, OX3 7FZ, UK.
Nat Commun. 2024 Apr 27;15(1):3580. doi: 10.1038/s41467-024-47680-z.
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.
癌症的致死性、化疗耐药性和转移特性与表型可塑性癌症干细胞（CSCs）相关。非细胞自主信号通路和细胞自主转录机制如何协调CSCs的干细胞样特性仍知之甚少。在此，我们使用定量蛋白质组学方法来鉴定胰腺癌中CSCs分泌的蛋白质。我们发现，细胞自主的E2F1/4-pRb/RBL2轴在健康导管细胞中平衡非细胞自主信号，但在KRAS突变后失调。E2F1和E2F4诱导而pRb/RBL2降低WNT配体表达（如WNT7A、WNT7B、WNT10A、WNT4），从而调节胰腺癌和乳腺癌中CSCs的自我更新、化疗耐药性和侵袭性，以及成纤维细胞增殖。对表观遗传酶的筛选确定GCN5是CSCs的调节因子，它将H3K9ac沉积到WNT启动子和增强子上。总的来说，旁分泌信号通路在多种癌症中受E2F-GCN5-RB轴控制，这可能是消除CSCs的治疗靶点。
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