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Dhimolea E , de Matos Simoes R , Kansara D , Al'Khafaji A , Bouyssou J , Weng X , Sharma S , Raja J , Awate P , Shirasaki R , Tang H , Glassner BJ , Liu Z , Gao D , Bryan J , Bender S , Roth J , Scheffer M , Jeselsohn R , Gray NS , Georgakoudi I , Vazquez F , Tsherniak A , Chen Y , Welm A , Duy C , Melnick A , Bartholdy B , Brown M , Culhane AC , Mitsiades CS
An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence
Cancer Cell. 2021 feb 8;39(2) :240-256 e11
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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.
1878-3686 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 R01 CA179483/CA/NCI NIH HHS/United States Journal Article United States Cancer Cell. 2021 Jan 5:S1535-6108(20)30609-7. doi: 10.1016/j.ccell.2020.12.002.