Temporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer.

Adenocarcinoma / genetics Animals Carcinoma, Neuroendocrine / genetics Cell Line, Tumor Disease Progression Gene Expression Regulation, Neoplastic Humans Male Mice, Inbred C57BL Mice, Knockout Mice, Transgenic N-Myc Proto-Oncogene Protein / genetics Organ Culture Techniques / methods Prognosis Prostate / metabolism Prostatic Neoplasms / genetics Receptors, Androgen / genetics Retinoblastoma Protein / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
07 06 2021
Historique:
received: 20 09 2020
accepted: 11 05 2021
entrez: 8 6 2021
pubmed: 9 6 2021
medline: 29 6 2021
Statut: epublish

Résumé

Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.

Identifiants

DOI: 10.1038/s41467-021-23780-y PMID: 34099734 PMC: PMC8185096
pubmed: 34099734
doi: 10.1038/s41467-021-23780-y
pii: 10.1038/s41467-021-23780-y
pmc: PMC8185096
doi:

Substances chimiques

N-Myc Proto-Oncogene Protein 0
Receptors, Androgen 0
Retinoblastoma Protein 0

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

3372

Subventions

Organisme : NCI NIH HHS
ID : P50 CA211024
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA230913
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA203702
Pays : United States

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Auteurs

Nicholas J Brady (NJ)

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
ORCID: 0000-0002-2928-0232

Alyssa M Bagadion (AM)

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
ORCID: 0000-0001-8577-4395

Richa Singh (R)

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.

Vincenza Conteduca (V)

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

Lucie Van Emmenis (L)

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.

Elisa Arceci (E)

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
ORCID: 0000-0001-9962-7513

Hubert Pakula (H)

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.

Ryan Carelli (R)

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.

Francesca Khani (F)

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
Department of Urology, Weill Cornell Medicine, New York, NY, USA.
Caryl and Israel Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA.
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
ORCID: 0000-0001-7238-8604

Martin Bakht (M)

Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
ORCID: 0000-0001-8803-2485

Michael Sigouros (M)

Caryl and Israel Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA.
ORCID: 0000-0002-0328-8359

Rohan Bareja (R)

Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.

Andrea Sboner (A)

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
Caryl and Israel Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA.
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.

Olivier Elemento (O)

Caryl and Israel Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA.
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.

Scott Tagawa (S)

Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
ORCID: 0000-0003-2777-8587

David M Nanus (DM)

Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
Department of Medicine, Weill Cornell Medicine, New York, NY, USA.

Massimo Loda (M)

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.

Himisha Beltran (H)

Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
ORCID: 0000-0003-3259-2226

Brian Robinson (B)

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
Department of Urology, Weill Cornell Medicine, New York, NY, USA.
Caryl and Israel Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA.
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
ORCID: 0000-0001-5374-890X

David S Rickman (DS)

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. dsr2005@med.cornell.edu.
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. dsr2005@med.cornell.edu.
ORCID: 0000-0001-7420-5883

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Classifications MeSH

questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Adénocarcinome › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Eucaryotes › Animaux › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroendocrines › Carcinome neuroendocrine › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Évolution de la maladie › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique et à glissière à leucines › Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines › Protéine du proto-oncogène N-Myc › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Techniques d'investigation › Techniques in vitro › Techniques de culture › Techniques de culture d'organes › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Diagnostic › Pronostic › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Tissus › Glandes exocrines › Prostate › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital mâle › Tumeurs de la prostate › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Récepteurs aux androgènes › Temporal evolution of cellular heterogeneity...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Phosphoprotéines › Protéine du rétinoblastome › Temporal evolution of cellular heterogeneity...