5-Azacytidine- and retinoic-acid-induced reprogramming of DCCs into dormancy suppresses metastasis via restored TGF-β-SMAD4 signaling.
5-Azacytidine- and retinoic-acid-induced reprogramming of DCCs into dormancy suppresses metastasis via restored TGF-β-SMAD4 signaling.
复制标题
DOI：
10.1016/j.celrep.2023.112560
复制
发表时间：
2023-06-27
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
继发性器官中的播散性癌细胞（DCC）可以在重新激活进入明显转移之前保持休眠数年至数十年。导致癌细胞染色质重塑和转录重编程的微环境信号似乎控制了休眠的发生和逃逸。在这里，我们揭示了DNA甲基化抑制剂5-氮杂胞苷（AZA）和视黄酸受体配体全反式视黄酸（atRA）或AM 80（RARα特异性激动剂）的治疗组合促进癌细胞的稳定休眠。用AZA+atRA治疗头颈部鳞状细胞癌（HNSCC）或乳腺癌细胞诱导SMAD 2/3/4依赖性转录程序，其恢复转化生长因子β（TGF-β）信号传导和抗增殖功能。值得注意的是，AZA+atRA或AZA+ AM 80的任一组合通过诱导和维持孤立的DCC处于SMAD 4 +/NR 2F 1+非增殖状态而强烈抑制HNSCC肺转移形成。值得注意的是，SMAD 4敲低足以驱动对AZA+ atRA诱导的休眠的抗性。我们的结论是，治疗剂量的AZA和RAR激动剂可以诱导和/或维持休眠，并显着限制转移的发展。休眠的DCC的觉醒导致致命的转移性疾病。Singh等人表明，用5-氮杂胞苷随后用视黄酸对癌细胞进行新辅助+辅助治疗，通过增强的TGF-β-SMAD 4信号转导将恶性细胞重编程进入休眠状态来抑制转移。
Disseminated cancer cells (DCCs) in secondary organs can remain dormant for years to decades before re-activating into overt metastasis. Microenvironmental signals leading to cancer cell chromatin remodeling and transcriptional reprogramming appear to control onset and escape from dormancy. Here, we reveal that the therapeutic combination of the DNA methylation inhibitor 5-azacytidine (AZA) and the retinoic acid receptor ligands all-trans retinoic acid (atRA) or AM80, an RARα-specific agonist, promotes stable dormancy in cancer cells. Treatment of head and neck squamous cell carcinoma (HNSCC) or breast cancer cells with AZA+atRA induces a SMAD2/3/4-dependent transcriptional program that restores transforming growth factor β (TGF-β)-signaling and anti-proliferative function. Significantly, either combination, AZA+atRA or AZA+AM80, strongly suppresses HNSCC lung metastasis formation by inducing and maintaining solitary DCCs in a SMAD4+/NR2F1+ non-proliferative state. Notably, SMAD4 knockdown is sufficient to drive resistance to AZA+atRA-induced dormancy. We conclude that therapeutic doses of AZA and RAR agonists may induce and/or maintain dormancy and significantly limit metastasis development. Awakening of dormant DCCs leads to lethal metastatic disease. Singh et al. show that neo-adjuvant + adjuvant treatment of cancer cells with 5-azacytidine followed by retinoic acid suppresses metastasis by reprogramming malignant cells into dormancy via enhanced TGF-β-SMAD4 signaling.
登录
查看更多内容
影响因子：
22.7
作者：
Di Martino JS;Nobre AR;Mondal C;Taha I;Farias EF;Fertig EJ;Naba A;Aguirre-Ghiso JA;Bravo-Cordero JJ
通讯作者：
Bravo-Cordero JJ
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
4
作者：
Dillekas, Hanna;Rogers, Michael S.;Straume, Oddhjorn
通讯作者：
Straume, Oddhjorn
影响因子：
5.8
作者：
Lachmann, Alexander;Xu, Huilei;Ma'ayan, Avi
通讯作者：
Ma'ayan, Avi
影响因子：
64.8
作者：
Harper KL;Sosa MS;Entenberg D;Hosseini H;Cheung JF;Nobre R;Avivar-Valderas A;Nagi C;Girnius N;Davis RJ;Farias EF;Condeelis J;Klein CA;Aguirre-Ghiso JA
通讯作者：
Aguirre-Ghiso JA