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An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence.
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.
Afiliação
  • Dhimolea E; 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. Electronic address: eugen_dhimolea@dfci.harvard.edu.
  • de Matos Simoes R; 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.
  • Kansara D; Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.
  • Al'Khafaji A; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bouyssou J; 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.
  • Weng X; Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA.
  • Sharma S; Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA.
  • Raja J; Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA.
  • Awate P; Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA.
  • Shirasaki R; 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.
  • Tang H; 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.
  • Glassner BJ; 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.
  • Liu Z; Department of Biomedical Engineering, Tufts University, Medford, MA, USA.
  • Gao D; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Bryan J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bender S; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Roth J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Scheffer M; 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.
  • Jeselsohn R; Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • Gray NS; Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • Georgakoudi I; Department of Biomedical Engineering, Tufts University, Medford, MA, USA.
  • Vazquez F; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Tsherniak A; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Chen Y; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Welm A; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • Duy C; Department of Medicine, Weill Cornell Medicine, New York, NY, USA; Cancer Signaling and Epigenetics Program, Institute for Cancer Research, Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA, USA.
  • Melnick A; Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
  • Bartholdy B; Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • Brown M; Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • Culhane AC; Department of Data Sciences, Dana-Farber Cancer Institute & Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Mitsiades CS; 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. Electronic address: constantine_mitsiades@dfci.harvard.edu.
Cancer Cell ; 39(2): 240-256.e11, 2021 02 08.
Article em En | MEDLINE | ID: mdl-33417832
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Adaptação Fisiológica / Proteínas Proto-Oncogênicas c-myc / Embrião de Mamíferos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Cancer Cell Assunto da revista: NEOPLASIAS Ano de publicação: 2021 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Adaptação Fisiológica / Proteínas Proto-Oncogênicas c-myc / Embrião de Mamíferos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Cancer Cell Assunto da revista: NEOPLASIAS Ano de publicação: 2021 Tipo de documento: Article