Interferon-dependent SLC14A1+ cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer
Interferon-dependent SLC14A1+ cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer
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DOI：
10.1016/j.ccell.2022.11.005
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发表时间：
2022-12-12
期刊：
影响因子：
50.3
通讯作者：
Liu, Zhuowei
中科院分区：
文献类型：
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作者：
Ma, Zikun;Li, Xiangdong;Liu, Zhuowei
癌症相关成纤维细胞（CAF）在响应癌症治疗和患者预后中发挥作用。CAFs表现出表型和功能的异质性，在不同组织来源的肿瘤中差异很大。在这里，我们使用膀胱癌（BC）患者样本的单细胞RNA测序，并报告了一个CAF亚群，其特征是尿素转运蛋白SLC 14 A1的过表达。该群体由干扰素信号传导诱导，并通过WNT 5A旁分泌途径赋予BC细胞干性。肿瘤细胞中cGAS-STING信号的激活驱动干扰素的产生，从而揭示了cGAS-STING信号与SLC 14 A1（+）CAF分化之间的联系。此外，通过靶向STAT 1或STING抑制SLC 14 A1（+）CAF形成使肿瘤细胞对化疗敏感。更重要的是，具有高比例瘤内SLC 14 A1（+）CAF的BC患者显示出与癌症分期无关的不良结局，并且对新辅助化疗或免疫治疗的反应率更差。
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 subpop-ulation characterized by overexpression of the urea transporter SLC14A1. This population is induced by inter-feron 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 tar-geting of STAT1 or STING sensitizes tumor cells to chemotherapy. More important, BC patients with high pro-portions of intratumoral SLC14A1(+) CAFs show cancer stage-independent poor outcome and a worse response rate to neoadjuvant chemotherapy or immunotherapy.