Dong Guoying, Wang Qin, Wen Mingxin, Xia Zhongkun, Zhang Shujun, Gao Wei, Wang Huaizhi, Wei Guangwei, Wang Yunshan
Department of Anatomy, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China.
Oncogene. 2023 Sep;42(40):3000-3014. doi: 10.1038/s41388-023-02817-0. Epub 2023 Aug 24.
Pancreatic ductal adenocarcinoma (PDAC) resists to current treatments due to its inherent tumor heterogeneity, therapy-resistant cancer stem/initiating cells survival, and immune evasion in the immunosuppressive tumor microenvironment (TME). Here, the results show that clinical PDAC and adjacent tissues undergo distinct chromatin remodeling. Multiple omics analysis revealed DEAD-box RNA helicase 18 (DDX18), a carcinogenic gene with similar H3K4me3 profile, is up-regulated and correlates with poor survival in PDAC patients. We validated that DDX18 deposits on the STAT1 promoter region and counteracts H3K27me3 deposition on the STAT1 promoter sequence by modulating the formation of the PRC2 complex to up-regulate the expression of STAT1, which results in the up-regulation of PD-L1 expression, T lymphocyte accumulation and overactivation in the highly desmoplastic and immunosuppressive pancreatic TME. DDX18-STAT1 axis inhibition also affects stemness of cancer cells, epithelial-mesenchymal transition (EMT) and disrupts the immunosuppressive TME simultaneously, producing sustained remissions of aggressive PDAC by synergizing with anti-PD-L1 therapy. Combining DDX18 inhibition with anti-PD-L1 immunochemotherapy to treat PDAC patients will pave a new way for clinical treatment of patients with PDAC. This study found that clinical PDAC and adjacent pancreatic tissues undergo distinct chromatin remodeling featured by the upregulation of DEAD-box RNA helicase 18 (DDX18). We further validated that DDX18 deposits on the STAT1 promoter region and counteracts H3K27me3 deposition on the STAT1 promoter by modulating the formation of the PRC2 complex to up-regulate the expression of STAT1. DDX18-STAT1 axis enhances the stemness of cancer cells, the upregulation of PD-L1 expression, T lymphocyte accumulation and overactivation in the highly desmoplastic and immunosuppressive pancreatic TME.
胰腺导管腺癌（PDAC）由于其固有的肿瘤异质性、治疗抗性癌症干细胞/起始细胞存活以及免疫抑制性肿瘤微环境（TME）中的免疫逃逸，对当前治疗具有抗性。在此，结果表明临床PDAC和相邻组织经历了不同的染色质重塑。多组学分析显示，具有相似H3K4me3图谱的致癌基因DEAD盒RNA解旋酶18（DDX18）上调，且与PDAC患者的不良生存相关。我们验证了DDX18沉积在STAT1启动子区域，并通过调节PRC2复合物的形成来抵消STAT1启动子序列上的H3K27me3沉积，从而上调STAT1的表达，这导致PD-L1表达上调、T淋巴细胞在高度促纤维增生性和免疫抑制性胰腺TME中积累和过度活化。抑制DDX18-STAT1轴还会影响癌细胞的干性、上皮-间质转化（EMT），并同时破坏免疫抑制性TME，通过与抗PD-L1疗法协同作用，使侵袭性PDAC产生持续缓解。将DDX18抑制与抗PD-L1免疫化疗联合用于治疗PDAC患者将为PDAC患者的临床治疗开辟一条新途径。本研究发现，临床PDAC和相邻胰腺组织经历了不同的染色质重塑，其特征是DEAD盒RNA解旋酶18（DDX18）上调。我们进一步验证了DDX18沉积在STAT1启动子区域，并通过调节PRC2复合物的形成来抵消STAT1启动子上的H3K27me3沉积，从而上调STAT1的表达。DDX18-STAT1轴增强了癌细胞的干性、PD-L1表达上调、T淋巴细胞在高度促纤维增生性和免疫抑制性胰腺TME中的积累和过度活化。
