Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts.
Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts.
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DOI：
10.1016/j.xcrm.2022.100541
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发表时间：
2022-06-21
影响因子：
14.3
通讯作者：
Underwood, Timothy J.
中科院分区：
文献类型：
--
作者：
Sharpe, Benjamin P.;Hayden, Annette;Manousopoulou, Antigoni;Cowie, Andrew;Walker, Robert C.;Harrington, Jack;Izadi, Fereshteh;Breininger, Stella P.;Gibson, Jane;Pickering, Oliver;Jaynes, Eleanor;Kyle, Ewan;Saunders, John H.;Parsons, Simon L.;Ritchie, Alison A.;Clarke, Philip A.;Collier, Pamela;Mongan, Nigel P.;Bates, David O.;Yacqub-Usman, Kiren;Garbis, Spiros D.;Walters, Zoe;Rose-Zerilli, Matthew;Grabowska, Anna M.;Underwood, Timothy J.
食管腺癌（EAC）的化疗耐药是由肿瘤微环境（TME）的癌细胞外在机制支持的。我们证明，通过用磷酸二酯酶5型抑制剂（PDE 5i）靶向主要TME细胞类型癌症相关成纤维细胞（CAF）的肿瘤促进功能，我们可以提高标准治疗化疗的疗效。在离体条件下，PDE 5i阻止正常成纤维细胞向CAF的转分化，并消除已建立的EAC CAF的促肿瘤功能。使用鸟枪蛋白质组学和单细胞RNA-seq，我们揭示了与成纤维细胞活化和肿瘤促进相关的途径的PDE 5i特异性调节。最后，我们在接近患者和体内基于PDX的模型系统中证实了PDE 5i与化疗联合的疗效。这些研究结果表明，CAF在EAC中驱动化疗耐药性，并且可以通过重新利用PDE 5i来靶向，PDE 5i是一种安全且耐受性良好的药物，用于全球数百万患者治疗勃起功能障碍。癌症相关成纤维细胞（CAFs）驱动EAC耐药性磷酸二酯酶5型抑制剂（PDE 5i）靶向CAFs的促肿瘤功能PDE 5i增强EAC三维肿瘤模型中化疗的疗效一项关于PDE 5i联合化疗治疗食管癌的随机试验目前需要进行食管腺癌对标准治疗化疗的耐药性取决于肿瘤微环境的癌细胞外在机制。Sharpe等人显示将PDE 5抑制剂重新用于靶向癌症相关成纤维细胞的肿瘤促进功能增强了3D肿瘤模型中化疗的功效
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. Cancer-associated fibroblasts (CAFs) drive EAC resistance Phosphodiesterase type 5 inhibitors (PDE5i) target the tumor-promoting function of CAFs PDE5i enhance the efficacy of chemotherapy in 3D-tumor models of EAC A randomized trial of PDE5i with chemotherapy in esophageal cancer is now required Resistance to standard-of-care chemotherapy in esophageal adenocarcinoma is dependent on cancer cell extrinsic mechanisms of the tumor microenvironment. Sharpe et al. show that repurposing PDE5 inhibitors to target the tumor-promoting function of cancer-associated fibroblasts enhances the efficacy of chemotherapy in 3D-tumor models
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
13.5
作者：
Das, Anindita;Durrant, David;Salloum, Fadi N.;Xi, Lei;Kukreja, Rakesh C.
通讯作者：
Kukreja, Rakesh C.
DOI：
10.18632/aging.101355
发表时间：
2017-12-28
期刊：
Aging
影响因子：
--
作者：
Bhome R;Goh RW;Bullock MD;Pillar N;Thirdborough SM;Mellone M;Mirnezami R;Galea D;Veselkov K;Gu Q;Underwood TJ;Primrose JN;De Wever O;Shomron N;Sayan AE;Mirnezami AH
通讯作者：
Mirnezami AH
影响因子：
0.7
作者：
Desmoulière, A;Guyot, C;Gabbiani, C
通讯作者：
Gabbiani, C
影响因子：
45.3
作者：
Allum, William H.;Stenning, Sally P.;Langley, Ruth E.
通讯作者：
Langley, Ruth E.