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

Adaptation, Physiological / drug effects Animals Antineoplastic Agents / pharmacology Apoptosis / genetics Cell Line Cell Line, Tumor Cyclin-Dependent Kinase 9 / genetics Diapause / drug effects Embryo, Mammalian / drug effects Female HEK293 Cells Humans MCF-7 Cells Mice Proto-Oncogene Proteins c-myc / genetics Transcription Factors / genetics Transcription, Genetic / genetics Up-Regulation / drug effects
CDK9 CRISPR MYC adaptation to stress breast cancer cancer diapause drug persistence prostate cancer residual tumor

Journal

Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617

Informations de publication

Date de publication:
08 02 2021
Historique:
received: 31 01 2020
revised: 19 10 2020
accepted: 02 12 2020
pubmed: 9 1 2021
medline: 29 9 2021
entrez: 8 1 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ccell.2020.12.002 PMID: 33417832 PMC: PMC8670073
pubmed: 33417832
pii: S1535-6108(20)30609-7
doi: 10.1016/j.ccell.2020.12.002
pmc: PMC8670073
mid: NIHMS1662675
pii:
doi:

Substances chimiques

Antineoplastic Agents 0
Proto-Oncogene Proteins c-myc 0
Transcription Factors 0
Cyclin-Dependent Kinase 9 EC 2.7.11.22

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

240-256.e11

Subventions

Organisme : NCRR NIH HHS
ID : S10 RR028832
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA179483
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA208100
Pays : United States
Organisme : Department of Defense

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests E.D. and C.S.M. are co-inventors on a patent related to the use of 3D cultures. Y.C. reports personal fees from Oric Pharmaceuticals outside the submitted work. R.J. reports research funding from Pfizer and Lilly and consulting for Carrick and Luminex. M.B. reports sponsored research support from Novartis; serves on the science advisory board (SAB) of and received fees from Kronos Bio, GV20 Oncotherapy, and H3 Biomedicine; and holds equity in Kronos Bio and GV20 Oncotherapy. N.S.G. is a founder, SAB member, and equity holder in Gatekeeper, Syros, Petra, C4, Allorion, Jengu, Inception, B2S, and Soltego (board member) and his lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Her2llc, Deerfield, and Sanofi. C.S.M. discloses research funding from Janssen/Johnson & Johnson, Teva, EMD Serono, Abbvie, Arch Oncology, Karyopharm, Sanofi, and Nurix; employment of a relative with Takeda; and consultant/honoraria from Fate Therapeutics, Ionis Pharmaceuticals, and FIMECS.

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Auteurs

Eugen 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.

Ricardo 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.

Dhvanir Kansara (D)

Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.

Aziz Al'Khafaji (A)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Juliette 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.

Xiang Weng (X)

Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA.

Shruti Sharma (S)

Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA.

Joseline Raja (J)

Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA.

Pallavi Awate (P)

Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA.

Ryosuke 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.

Huihui 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.

Brian J 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.

Zhiyi Liu (Z)

Department of Biomedical Engineering, Tufts University, Medford, MA, USA.

Dong Gao (D)

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Jordan Bryan (J)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Samantha Bender (S)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Jennifer Roth (J)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Michal 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.

Rinath Jeselsohn (R)

Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Harvard Medical School, Boston, MA, USA.

Nathanael S Gray (NS)

Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Harvard Medical School, Boston, MA, USA.

Irene Georgakoudi (I)

Department of Biomedical Engineering, Tufts University, Medford, MA, USA.

Francisca Vazquez (F)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Aviad Tsherniak (A)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Yu Chen (Y)

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Alana Welm (A)

Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Cihangir 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.

Ari Melnick (A)

Department of Medicine, Weill Cornell Medicine, New York, NY, USA.

Boris Bartholdy (B)

Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Myles Brown (M)

Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Harvard Medical School, Boston, MA, USA.

Aedin C Culhane (AC)

Department of Data Sciences, Dana-Farber Cancer Institute & Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Constantine S 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.

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Classifications MeSH

questionsmedicales.fr › Phénomènes biologiques › Adaptation biologique › Adaptation physiologique › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Eucaryotes › Animaux › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs d'élongation transcriptionnelle › Facteur B d'élongation transcriptionnelle positive › Kinase-9 cycline-dépendante › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Morphogenèse › Métamorphose biologique › Étapes du cycle de vie › Diapause › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Structures de l'embryon › Embryon de mammifère › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › Cellules MCF-7 › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique hélice-boucle-hélice › Protéines proto-oncogènes c-myc › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Phénomènes génétiques › Expression des gènes › Transcription génétique › An Embryonic Diapause-like Adaptation with...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Régulation positive › An Embryonic Diapause-like Adaptation with...