Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Urology, Guangzhou 510060, China.
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Pancreatobiliary Surgery, Guangzhou 510060, China.
Cancer Cell. 2022 Dec 12;40(12):1550-1565.e7. doi: 10.1016/j.ccell.2022.11.005. Epub 2022 Dec 1.
Cancer-associated fibroblasts (CAFs) play a role in response to cancer treatment and patient prognosis. CAFs show phenotypic and functional heterogeneity and differ widely in tumors of different tissue origin. Here, we use single-cell RNA sequencing of bladder cancer (BC) patient samples and report a CAF subpopulation characterized by overexpression of the urea transporter SLC14A1. This population is induced by interferon signaling and confers stemness to BC cells via the WNT5A paracrine pathway. Activation of cGAS-STING signaling in tumor cells drives interferon production, thereby revealing a link between cGAS-STING signaling and SLC14A1 CAF differentiation. Furthermore, the inhibition of SLC14A1 CAF formation via targeting of STAT1 or STING sensitizes tumor cells to chemotherapy. More important, BC patients with high proportions of intratumoral SLC14A1 CAFs show cancer stage-independent poor outcome and a worse response rate to neoadjuvant chemotherapy or immunotherapy.
癌症相关成纤维细胞 (CAFs) 在癌症治疗和患者预后方面发挥作用。CAFs 表现出表型和功能异质性，在不同组织来源的肿瘤中差异很大。在这里，我们对膀胱癌 (BC) 患者样本进行了单细胞 RNA 测序，并报告了一个特征为尿素转运蛋白 SLC14A1 过表达的 CAF 亚群。该群体由干扰素信号诱导，通过 WNT5A 旁分泌途径赋予 BC 细胞干性。肿瘤细胞中 cGAS-STING 信号的激活会导致干扰素的产生，从而揭示了 cGAS-STING 信号与 SLC14A1 CAF 分化之间的联系。此外，通过靶向 STAT1 或 STING 抑制 SLC14A1 CAF 的形成可使肿瘤细胞对化疗更敏感。更重要的是，肿瘤内 SLC14A1 CAF 比例较高的 BC 患者表现出与癌症分期无关的不良预后和对新辅助化疗或免疫治疗的反应率更差。
