Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
Experimental Drug Development Centre, A*Star, Singapore, Singapore.
EMBO Mol Med. 2021 Apr 9;13(4):e13349. doi: 10.15252/emmm.202013349. Epub 2021 Mar 4.
Wnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have proven effective in Wnt-addicted preclinical cancer models and are in clinical trials. In a survey for potential combination therapies, we found that Wnt inhibition synergizes with the PARP inhibitor olaparib in Wnt-addicted cancers. Mechanistically, we find that multiple genes in the homologous recombination and Fanconi anemia repair pathways, including BRCA1, FANCD2, and RAD51, are dependent on Wnt/β-catenin signaling in Wnt-high cancers, and treatment with a PORCN inhibitor creates a BRCA-like state. This coherent regulation of DNA repair genes occurs in part via a Wnt/β-catenin/MYBL2 axis. Importantly, this pathway also functions in intestinal crypts, where high expression of BRCA and Fanconi anemia genes is seen in intestinal stem cells, with further upregulation in Wnt-high APC mutant polyps. Our findings suggest a general paradigm that Wnt/β-catenin signaling enhances DNA repair in stem cells and cancers to maintain genomic integrity. Conversely, interventions that block Wnt signaling may sensitize cancers to radiation and other DNA damaging agents.
Wnt 信号通路维持多种成体干细胞区室，并与癌症的化疗耐药性有关。阻断 Wnt 分泌的 PORCN 抑制剂已被证明在依赖 Wnt 的临床前癌症模型中有效，且正在临床试验中。在一项针对潜在联合治疗的调查中，我们发现 Wnt 抑制与 PARP 抑制剂奥拉帕利在依赖 Wnt 的癌症中具有协同作用。从机制上讲，我们发现同源重组和范可尼贫血修复途径中的多个基因，包括 BRCA1、FANCD2 和 RAD51，在 Wnt 高表达的癌症中依赖于 Wnt/β-连环蛋白信号通路，而 PORCN 抑制剂的治疗会产生类似于 BRCA 的状态。这种 DNA 修复基因的协调调控部分是通过 Wnt/β-连环蛋白/MYBL2 轴发生的。重要的是，该途径也存在于肠隐窝中，在肠干细胞中观察到 BRCA 和范可尼贫血基因的高表达，而在 Wnt 高表达 APC 突变息肉中进一步上调。我们的研究结果表明，Wnt/β-连环蛋白信号通路增强了干细胞和癌症中的 DNA 修复，以维持基因组完整性。相反，阻断 Wnt 信号通路的干预措施可能会使癌症对辐射和其他 DNA 损伤剂敏感。
