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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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 |
format | Article |
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[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.</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccell.2020.12.002</identifier><identifier>PMID: 33417832</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>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</subject><ispartof>Cancer cell, 2021-02, Vol.39 (2), p.240-256.e11</ispartof><rights>2020 Elsevier Inc.</rights><rights>Copyright © 2020 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-86985c867818732388f8eebc0afbeae19a6352008142c19a4abd092f52abb17f3</citedby><cites>FETCH-LOGICAL-c459t-86985c867818732388f8eebc0afbeae19a6352008142c19a4abd092f52abb17f3</cites><orcidid>0000-0001-9839-8448 ; 0000-0001-7996-7529 ; 0000-0002-0171-3884 ; 0000-0002-7401-8591</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ccell.2020.12.002$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3548,27922,27923,45993</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33417832$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dhimolea, Eugen</creatorcontrib><creatorcontrib>de Matos Simoes, Ricardo</creatorcontrib><creatorcontrib>Kansara, Dhvanir</creatorcontrib><creatorcontrib>Al’Khafaji, Aziz</creatorcontrib><creatorcontrib>Bouyssou, Juliette</creatorcontrib><creatorcontrib>Weng, Xiang</creatorcontrib><creatorcontrib>Sharma, Shruti</creatorcontrib><creatorcontrib>Raja, Joseline</creatorcontrib><creatorcontrib>Awate, Pallavi</creatorcontrib><creatorcontrib>Shirasaki, Ryosuke</creatorcontrib><creatorcontrib>Tang, Huihui</creatorcontrib><creatorcontrib>Glassner, Brian J.</creatorcontrib><creatorcontrib>Liu, Zhiyi</creatorcontrib><creatorcontrib>Gao, Dong</creatorcontrib><creatorcontrib>Bryan, Jordan</creatorcontrib><creatorcontrib>Bender, Samantha</creatorcontrib><creatorcontrib>Roth, Jennifer</creatorcontrib><creatorcontrib>Scheffer, Michal</creatorcontrib><creatorcontrib>Jeselsohn, Rinath</creatorcontrib><creatorcontrib>Gray, Nathanael S.</creatorcontrib><creatorcontrib>Georgakoudi, Irene</creatorcontrib><creatorcontrib>Vazquez, Francisca</creatorcontrib><creatorcontrib>Tsherniak, Aviad</creatorcontrib><creatorcontrib>Chen, Yu</creatorcontrib><creatorcontrib>Welm, Alana</creatorcontrib><creatorcontrib>Duy, Cihangir</creatorcontrib><creatorcontrib>Melnick, Ari</creatorcontrib><creatorcontrib>Bartholdy, Boris</creatorcontrib><creatorcontrib>Brown, Myles</creatorcontrib><creatorcontrib>Culhane, Aedin C.</creatorcontrib><creatorcontrib>Mitsiades, Constantine S.</creatorcontrib><title>An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><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.</description><subject>adaptation to stress</subject><subject>Adaptation, Physiological - drug effects</subject><subject>Adaptation, Physiological - genetics</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - genetics</subject><subject>breast cancer</subject><subject>cancer</subject><subject>CDK9</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>CRISPR</subject><subject>Cyclin-Dependent Kinase 9 - genetics</subject><subject>diapause</subject><subject>Diapause - drug effects</subject><subject>Diapause - genetics</subject><subject>drug persistence</subject><subject>Embryo, Mammalian - drug effects</subject><subject>Embryo, Mammalian - physiology</subject><subject>Female</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>MCF-7 Cells</subject><subject>Mice</subject><subject>MYC</subject><subject>prostate cancer</subject><subject>Proto-Oncogene Proteins c-myc - genetics</subject><subject>residual tumor</subject><subject>Transcription Factors - genetics</subject><subject>Transcription, Genetic - genetics</subject><subject>Up-Regulation - drug effects</subject><subject>Up-Regulation - genetics</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UctO3DAUtVAr3l-AVHnJJoMfieMsqDSCASpRtRLTteU4N8VDEqe2M2j-Hk8HUNl05dd5XJ-D0BklM0qouFjNjIGumzHC0g2bEcL20CGVpcy4kOJT2he8yAQl8gAdhbAiiUXLah8dcJ7TUnJ2iNr5gBd97TdusAZfWz3qKUDW2SfA80aPUUfrBvxs4yN-mMbRQwjQ4O8bg-cm2rWNG7wYdN1BwMupdx4vPejYwxDxT_DBhgiDgRP0udVdgNPX9Rj9ulksr-6y-x-3367m95nJiypmUlSyMFKUMn2DMy5lKwFqQ3RbgwZaacELRoikOTPplOu6IRVrC6brmpYtP0Zfd7rjVPfQmDSG150ave213yinrfr4MthH9dutVfIkpORJ4PxVwLs_E4Soehu2MesB3BQUy0tRCCZEmaB8BzXeheChfbehRG0bUiv1tyG1bUhRplJDifXl3wnfOW-VJMDlDgApp7UFr4Kx2wwb68FE1Tj7X4MXAfelHQ</recordid><startdate>20210208</startdate><enddate>20210208</enddate><creator>Dhimolea, Eugen</creator><creator>de Matos Simoes, Ricardo</creator><creator>Kansara, Dhvanir</creator><creator>Al’Khafaji, Aziz</creator><creator>Bouyssou, Juliette</creator><creator>Weng, Xiang</creator><creator>Sharma, Shruti</creator><creator>Raja, Joseline</creator><creator>Awate, Pallavi</creator><creator>Shirasaki, Ryosuke</creator><creator>Tang, Huihui</creator><creator>Glassner, Brian J.</creator><creator>Liu, Zhiyi</creator><creator>Gao, Dong</creator><creator>Bryan, Jordan</creator><creator>Bender, Samantha</creator><creator>Roth, Jennifer</creator><creator>Scheffer, Michal</creator><creator>Jeselsohn, Rinath</creator><creator>Gray, Nathanael S.</creator><creator>Georgakoudi, Irene</creator><creator>Vazquez, Francisca</creator><creator>Tsherniak, Aviad</creator><creator>Chen, Yu</creator><creator>Welm, Alana</creator><creator>Duy, Cihangir</creator><creator>Melnick, Ari</creator><creator>Bartholdy, Boris</creator><creator>Brown, Myles</creator><creator>Culhane, Aedin C.</creator><creator>Mitsiades, Constantine S.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><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></search><sort><creationdate>20210208</creationdate><title>An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence</title><author>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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-86985c867818732388f8eebc0afbeae19a6352008142c19a4abd092f52abb17f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>adaptation to stress</topic><topic>Adaptation, Physiological - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dhimolea, Eugen</au><au>de Matos Simoes, Ricardo</au><au>Kansara, Dhvanir</au><au>Al’Khafaji, Aziz</au><au>Bouyssou, Juliette</au><au>Weng, Xiang</au><au>Sharma, Shruti</au><au>Raja, Joseline</au><au>Awate, Pallavi</au><au>Shirasaki, Ryosuke</au><au>Tang, Huihui</au><au>Glassner, Brian J.</au><au>Liu, Zhiyi</au><au>Gao, Dong</au><au>Bryan, Jordan</au><au>Bender, Samantha</au><au>Roth, Jennifer</au><au>Scheffer, Michal</au><au>Jeselsohn, Rinath</au><au>Gray, Nathanael S.</au><au>Georgakoudi, Irene</au><au>Vazquez, Francisca</au><au>Tsherniak, Aviad</au><au>Chen, Yu</au><au>Welm, Alana</au><au>Duy, Cihangir</au><au>Melnick, Ari</au><au>Bartholdy, Boris</au><au>Brown, Myles</au><au>Culhane, Aedin C.</au><au>Mitsiades, Constantine S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2021-02-08</date><risdate>2021</risdate><volume>39</volume><issue>2</issue><spage>240</spage><epage>256.e11</epage><pages>240-256.e11</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>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.</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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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 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-09T18%3A27%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=An%20Embryonic%20Diapause-like%20Adaptation%20with%20Suppressed%20Myc%20Activity%20Enables%20Tumor%20Treatment%20Persistence&rft.jtitle=Cancer%20cell&rft.au=Dhimolea,%20Eugen&rft.date=2021-02-08&rft.volume=39&rft.issue=2&rft.spage=240&rft.epage=256.e11&rft.pages=240-256.e11&rft.issn=1535-6108&rft.eissn=1878-3686&rft_id=info:doi/10.1016/j.ccell.2020.12.002&rft_dat=%3Cproquest_pubme%3E2476562667%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2476562667&rft_id=info:pmid/33417832&rft_els_id=S1535610820306097&rfr_iscdi=true |