Dhimolea Eugen, de Matos Simoes Ricardo, Kansara Dhvanir, Al'Khafaji Aziz, Bouyssou Juliette, Weng Xiang, Sharma Shruti, Raja Joseline, Awate Pallavi, Shirasaki Ryosuke, Tang Huihui, Glassner Brian J, Liu Zhiyi, Gao Dong, Bryan Jordan, Bender Samantha, Roth Jennifer, Scheffer Michal, Jeselsohn Rinath, Gray Nathanael S, Georgakoudi Irene, Vazquez Francisca, Tsherniak Aviad, Chen Yu, Welm Alana, Duy Cihangir, Melnick Ari, Bartholdy Boris, Brown Myles, Culhane Aedin C, Mitsiades Constantine S
Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.
Cancer Cell. 2021 Feb 8;39(2):240-256.e11. doi: 10.1016/j.ccell.2020.12.002. Epub 2021 Jan 7.
Treatment-persistent residual tumors impede curative cancer therapy. To understand this cancer cell state we generated models of treatment persistence that simulate the residual tumors. We observe that treatment-persistent tumor cells in organoids, xenografts, and cancer patients adopt a distinct and reversible transcriptional program resembling that of embryonic diapause, a dormant stage of suspended development triggered by stress and associated with suppressed Myc activity and overall biosynthesis. In cancer cells, depleting Myc or inhibiting Brd4, a Myc transcriptional co-activator, attenuates drug cytotoxicity through a dormant diapause-like adaptation with reduced apoptotic priming. Conversely, inducible Myc upregulation enhances acute chemotherapeutic activity. Maintaining residual cells in dormancy after chemotherapy by inhibiting Myc activity or interfering with the diapause-like adaptation by inhibiting cyclin-dependent kinase 9 represent potential therapeutic strategies against chemotherapy-persistent tumor cells. Our study demonstrates that cancer co-opts a mechanism similar to diapause with adaptive inactivation of Myc to persist during treatment.
治疗后持续存在的残留肿瘤阻碍了癌症的根治性治疗。为了解这种癌细胞状态，我们构建了模拟残留肿瘤的治疗持续性模型。我们观察到，类器官、异种移植模型及癌症患者体内治疗后持续存在的肿瘤细胞采用了一种独特且可逆的转录程序，类似于胚胎滞育，这是一种由应激触发的发育暂停休眠阶段，与Myc活性抑制和整体生物合成受抑制有关。在癌细胞中，敲除Myc或抑制Myc转录共激活因子Brd4，可通过类似滞育的休眠适应减少凋亡启动，从而减弱药物细胞毒性。相反，诱导性Myc上调可增强急性化疗活性。通过抑制Myc活性使化疗后残留细胞保持休眠，或通过抑制细胞周期蛋白依赖性激酶9干扰类似滞育的适应过程，是针对化疗后持续存在的肿瘤细胞的潜在治疗策略。我们的研究表明，癌症利用了一种类似于滞育的机制，通过Myc的适应性失活在治疗期间持续存在。
