School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK.
Proteas Bioanalytics, Torrance, CA 90502, USA.
Cell Rep Med. 2022 Jun 21;3(6):100541. doi: 10.1016/j.xcrm.2022.100541.
The chemotherapy resistance of esophageal adenocarcinomas (EACs) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that, by targeting the tumor-promoting functions of the predominant TME cell type, cancer-associated fibroblasts (CAFs) with phosphodiesterase type 5 inhibitors (PDE5i), we can enhance the efficacy of standard-of-care chemotherapy. In ex vivo conditions, PDE5i prevent the transdifferentiation of normal fibroblasts to CAF and abolish the tumor-promoting function of established EAC CAFs. Using shotgun proteomics and single-cell RNA-seq, we reveal PDE5i-specific regulation of pathways related to fibroblast activation and tumor promotion. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient and in vivo PDX-based model systems. These findings demonstrate that CAFs drive chemotherapy resistance in EACs and can be targeted by repurposing PDE5i, a safe and well-tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction.
食管腺癌 (EAC) 的化疗耐药性是由肿瘤微环境 (TME) 中癌细胞外在机制所支撑的。我们证明，通过靶向肿瘤促进功能最主要的 TME 细胞类型——癌症相关成纤维细胞 (CAF)，使用磷酸二酯酶 5 抑制剂 (PDE5i)，我们可以增强标准治疗化疗的疗效。在体外条件下，PDE5i 可防止正常成纤维细胞向 CAF 的转分化，并消除已建立的 EAC CAF 的肿瘤促进功能。通过蛋白质组学和单细胞 RNA-seq 分析，我们揭示了 PDE5i 对与成纤维细胞激活和肿瘤促进相关途径的特异性调控。最后，我们在接近患者的 PDX 模型系统和体内模型系统中证实了 PDE5i 联合化疗的疗效。这些发现表明，CAF 可导致 EAC 中的化疗耐药性，并且可以通过重新利用 PDE5i 来靶向治疗，PDE5i 是一种安全且耐受良好的药物类别，已在全球范围内为数百万患者用于治疗勃起功能障碍。
