美国丹娜-法伯癌症研究所Constantine S. Mitsiades、Eugen Dhimolea等研究人员合作发现，胚胎滞育样适应使肿瘤获得治疗耐受性。相关论文于2021年1月7日在线发表于国际学术期刊《癌细胞》。

据研究人员介绍，治疗耐受的残留肿瘤阻碍了癌症治愈。

为了了解这种癌细胞状态，研究人员生成了模拟残留肿瘤的治疗耐受模型。研究人员观察到类器官、异种移植和癌症患者中的治疗耐受性肿瘤细胞采用了与胚胎滞育相似的独特且可逆的转录程序；胚胎滞育是由压力触发的休眠发育阶段，与Myc活性和整体生物合成受到抑制有关。在癌细胞中，敲低Myc或抑制Myc转录共激活因子Brd4会通过休眠滞育样适应降低凋亡引发而减弱药物的细胞毒性。

相反，可诱导的Myc上调增强了急性化疗活性。通过抑制Myc活性使化疗后的残余细胞保持休眠状态或者通过抑制细胞周期蛋白依赖性激酶9来干扰滞育样适应可能是靶向化疗持久性肿瘤细胞的潜在治疗策略。

这项研究表明，癌症具有与滞育相似的机制，且Myc的适应性失活在治疗期间持续存在。

附：英文原文

Title: An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence

Author: Eugen Dhimolea, Ricardo de Matos Simoes, Dhvanir Kansara, Aziz Al’Khafaji, Juliette Bouyssou, Xiang Weng, Shruti Sharma, Joseline Raja, Pallavi Awate, Ryosuke Shirasaki, Huihui Tang, Brian J. Glassner, Zhiyi Liu, Dong Gao, Jordan Bryan, Samantha Bender, Jennifer Roth, Michal Scheffer, Rinath Jeselsohn, Nathanael S. Gray, Irene Georgakoudi, Francisca Vazquez, Aviad Tsherniak, Yu Chen, Alana Welm, Cihangir Duy, Ari Melnick, Boris Bartholdy, Myles Brown, Aedin C. Culhane, Constantine S. Mitsiades

Issue&Volume: 2021-01-07

Abstract: Treatment-persistent residual tumors impede curative cancer therapy. To understandthis cancer cell state we generated models of treatment persistence that simulatethe residual tumors. We observe that treatment-persistent tumor cells in organoids,xenografts, and cancer patients adopt a distinct and reversible transcriptional programresembling that of embryonic diapause, a dormant stage of suspended development triggeredby stress and associated with suppressed Myc activity and overall biosynthesis. Incancer cells, depleting Myc or inhibiting Brd4, a Myc transcriptional co-activator,attenuates drug cytotoxicity through a dormant diapause-like adaptation with reducedapoptotic priming. Conversely, inducible Myc upregulation enhances acute chemotherapeuticactivity. Maintaining residual cells in dormancy after chemotherapy by inhibitingMyc activity or interfering with the diapause-like adaptation by inhibiting cyclin-dependentkinase 9 represent potential therapeutic strategies against chemotherapy-persistenttumor cells. Our study demonstrates that cancer co-opts a mechanism similar to diapausewith adaptive inactivation of Myc to persist during treatment.

DOI: 10.1016/j.ccell.2020.12.002

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30609-7