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

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 an...

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Veröffentlicht in:Cancer cell 2021-02, Vol.39 (2), p.240-256.e11
Hauptverfasser: 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.
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container_end_page 256.e11
container_issue 2
container_start_page 240
container_title Cancer cell
container_volume 39
creator 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.
description 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. [Display omitted] •3D organoid cultures simulate the emergence of treatment-persistent residual tumors•Chemo-persister cells have suppressed Myc and a diapause-like molecular adaptation•Myc-suppressed cancer cells survive via reduced redox stress and apoptotic priming•CDK9 inhibition reverts biosynthetic pause and enhances chemosensitivity Dhimolea et al. document that cancer cell persistence during cytotoxic treatment is enabled by Myc inactivation and a biosynthetically paused adaptation resembling embryonic diapause. Myc-suppressed cancer cells have low redox stress and attenuated apoptotic priming. Interfering with this adaptive response of chemo-persistent cells enhances their chemosensitivity.
doi_str_mv 10.1016/j.ccell.2020.12.002
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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. [Display omitted] •3D organoid cultures simulate the emergence of treatment-persistent residual tumors•Chemo-persister cells have suppressed Myc and a diapause-like molecular adaptation•Myc-suppressed cancer cells survive via reduced redox stress and apoptotic priming•CDK9 inhibition reverts biosynthetic pause and enhances chemosensitivity Dhimolea et al. document that cancer cell persistence during cytotoxic treatment is enabled by Myc inactivation and a biosynthetically paused adaptation resembling embryonic diapause. Myc-suppressed cancer cells have low redox stress and attenuated apoptotic priming. 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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. [Display omitted] •3D organoid cultures simulate the emergence of treatment-persistent residual tumors•Chemo-persister cells have suppressed Myc and a diapause-like molecular adaptation•Myc-suppressed cancer cells survive via reduced redox stress and apoptotic priming•CDK9 inhibition reverts biosynthetic pause and enhances chemosensitivity Dhimolea et al. document that cancer cell persistence during cytotoxic treatment is enabled by Myc inactivation and a biosynthetically paused adaptation resembling embryonic diapause. Myc-suppressed cancer cells have low redox stress and attenuated apoptotic priming. 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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. [Display omitted] •3D organoid cultures simulate the emergence of treatment-persistent residual tumors•Chemo-persister cells have suppressed Myc and a diapause-like molecular adaptation•Myc-suppressed cancer cells survive via reduced redox stress and apoptotic priming•CDK9 inhibition reverts biosynthetic pause and enhances chemosensitivity Dhimolea et al. document that cancer cell persistence during cytotoxic treatment is enabled by Myc inactivation and a biosynthetically paused adaptation resembling embryonic diapause. Myc-suppressed cancer cells have low redox stress and attenuated apoptotic priming. Interfering with this adaptive response of chemo-persistent cells enhances their chemosensitivity.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>33417832</pmid><doi>10.1016/j.ccell.2020.12.002</doi><orcidid>https://orcid.org/0000-0001-9839-8448</orcidid><orcidid>https://orcid.org/0000-0001-7996-7529</orcidid><orcidid>https://orcid.org/0000-0002-0171-3884</orcidid><orcidid>https://orcid.org/0000-0002-7401-8591</orcidid><oa>free_for_read</oa></addata></record>
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1878-3686
language eng
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source MEDLINE; Cell Press Free Archives; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; ScienceDirect Journals (5 years ago - present)
subjects adaptation to stress
Adaptation, Physiological - drug effects
Adaptation, Physiological - genetics
Animals
Antineoplastic Agents - pharmacology
Apoptosis - genetics
breast cancer
cancer
CDK9
Cell Line
Cell Line, Tumor
CRISPR
Cyclin-Dependent Kinase 9 - genetics
diapause
Diapause - drug effects
Diapause - genetics
drug persistence
Embryo, Mammalian - drug effects
Embryo, Mammalian - physiology
Female
HEK293 Cells
Humans
MCF-7 Cells
Mice
MYC
prostate cancer
Proto-Oncogene Proteins c-myc - genetics
residual tumor
Transcription Factors - genetics
Transcription, Genetic - genetics
Up-Regulation - drug effects
Up-Regulation - genetics
title An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence
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