Genetic characterization of a unique neuroendocrine transdifferentiation prostate circulating tumor cell-derived eXplant model.

Animals Benzamides Carcinoma, Neuroendocrine / genetics Cell Line, Tumor Cell Transdifferentiation / genetics Disease Models, Animal Drug Resistance, Neoplasm Gene Expression Regulation, Neoplastic Homeodomain Proteins / metabolism Humans Male Mice Mice, Inbred NOD Neoplastic Cells, Circulating / drug effects Nitriles Phenylthiohydantoin / analogs & derivatives Phylogeny Prostate / metabolism Prostatic Neoplasms / genetics Receptors, Androgen / genetics Sequence Alignment Serine Endopeptidases / metabolism Transcription Factors / metabolism Transcriptome Tumor Suppressor Protein p53 / genetics

Journal

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

Informations de publication

Date de publication:
20 04 2020
Historique:
received: 11 01 2019
accepted: 04 03 2020
entrez: 22 4 2020
pubmed: 22 4 2020
medline: 5 8 2020
Statut: epublish

Résumé

Transformation of castration-resistant prostate cancer (CRPC) into an aggressive neuroendocrine disease (CRPC-NE) represents a major clinical challenge and experimental models are lacking. A CTC-derived eXplant (CDX) and a CDX-derived cell line are established using circulating tumor cells (CTCs) obtained by diagnostic leukapheresis from a CRPC patient resistant to enzalutamide. The CDX and the derived-cell line conserve 16% of primary tumor (PT) and 56% of CTC mutations, as well as 83% of PT copy-number aberrations including clonal TMPRSS2-ERG fusion and NKX3.1 loss. Both harbor an androgen receptor-null neuroendocrine phenotype, TP53, PTEN and RB1 loss. While PTEN and RB1 loss are acquired in CTCs, evolutionary analysis suggest that a PT subclone harboring TP53 loss is the driver of the metastatic event leading to the CDX. This CDX model provides insights on the sequential acquisition of key drivers of neuroendocrine transdifferentiation and offers a unique tool for effective drug screening in CRPC-NE management.

Identifiants

DOI: 10.1038/s41467-020-15426-2 PMID: 32313004 PMC: PMC7171138
pubmed: 32313004
doi: 10.1038/s41467-020-15426-2
pii: 10.1038/s41467-020-15426-2
pmc: PMC7171138
doi:

Substances chimiques

Benzamides 0
Homeodomain Proteins 0
NKX3-1 protein, human 0
Nitriles 0
Receptors, Androgen 0
TP53 protein, human 0
Transcription Factors 0
Tumor Suppressor Protein p53 0
Phenylthiohydantoin 2010-15-3
enzalutamide 93T0T9GKNU
Serine Endopeptidases EC 3.4.21.-
TMPRSS2 protein, human EC 3.4.21.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1884

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Auteurs

Vincent Faugeroux (V)

INSERM, U981 "Identification of Molecular Predictors and new Targets for Cancer Treatment", 94805, Villejuif, France.
Gustave Roussy, Université Paris-Saclay, "Circulating Tumor Cells" Translational Platform, CNRS UMS3655-INSERM US23 AMMICA, 94805, Villejuif, France.

Emma Pailler (E)

INSERM, U981 "Identification of Molecular Predictors and new Targets for Cancer Treatment", 94805, Villejuif, France.
Gustave Roussy, Université Paris-Saclay, "Circulating Tumor Cells" Translational Platform, CNRS UMS3655-INSERM US23 AMMICA, 94805, Villejuif, France.
ORCID: 0000-0002-7329-7429

Marianne Oulhen (M)

Gustave Roussy, Université Paris-Saclay, "Circulating Tumor Cells" Translational Platform, CNRS UMS3655-INSERM US23 AMMICA, 94805, Villejuif, France.

Olivier Deas (O)

XenTech, 91000, Evry, France.

Laura Brulle-Soumare (L)

XenTech, 91000, Evry, France.
ORCID: 0000-0003-3371-2496

Céline Hervieu (C)

INSERM, U981 "Identification of Molecular Predictors and new Targets for Cancer Treatment", 94805, Villejuif, France.
Gustave Roussy, Université Paris-Saclay, "Circulating Tumor Cells" Translational Platform, CNRS UMS3655-INSERM US23 AMMICA, 94805, Villejuif, France.

Virginie Marty (V)

Gustave Roussy, Université Paris-Saclay, Experimental and Translational Pathology Platform, CNRS UMS3655-INSERM US23 AMMICA, 94805, Villejuif, France.

Kamelia Alexandrova (K)

Gustave Roussy, Université Paris-Saclay, Department of Cell Therapy, 94805, Villejuif, France.

Kiki C Andree (KC)

Medical Cell Biophysics Group, Technical Medical Centre, Faculty of Science and Technology, University of Twente, 7522 NB, Enschede, The Netherlands.
ORCID: 0000-0002-7807-6289

Nikolas H Stoecklein (NH)

Department of General, Visceral and Pediatric Surgery, Medical Faculty, University Hospital of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
ORCID: 0000-0002-3412-594X

Dominique Tramalloni (D)

Gustave Roussy, Université Paris-Saclay, Department of Cell Therapy, 94805, Villejuif, France.

Stefano Cairo (S)

XenTech, 91000, Evry, France.
ORCID: 0000-0002-4725-5970

Maud NgoCamus (M)

Gustave Roussy, Université Paris-Saclay, Department of Cancer Medicine, 94805, Villejuif, France.

Claudio Nicotra (C)

Gustave Roussy, Université Paris-Saclay, Department of Cancer Medicine, 94805, Villejuif, France.

Leon W M M Terstappen (LWMM)

Medical Cell Biophysics Group, Technical Medical Centre, Faculty of Science and Technology, University of Twente, 7522 NB, Enschede, The Netherlands.
ORCID: 0000-0001-5944-3787

Nicolo Manaresi (N)

Menarini Silicon Biosystems S.p.A, 40013, Bologna, Italy.
ORCID: 0000-0002-1681-7037

Valérie Lapierre (V)

Gustave Roussy, Université Paris-Saclay, Department of Cell Therapy, 94805, Villejuif, France.

Karim Fizazi (K)

INSERM, U981 "Identification of Molecular Predictors and new Targets for Cancer Treatment", 94805, Villejuif, France.
Gustave Roussy, Université Paris-Saclay, Department of Cancer Medicine, 94805, Villejuif, France.

Jean-Yves Scoazec (JY)

Gustave Roussy, Université Paris-Saclay, Experimental and Translational Pathology Platform, CNRS UMS3655-INSERM US23 AMMICA, 94805, Villejuif, France.
ORCID: 0000-0003-1604-6823

Yohann Loriot (Y)

Gustave Roussy, Université Paris-Saclay, Department of Cancer Medicine, 94805, Villejuif, France. Yohann.loriot@gustaveroussy.fr.

Jean-Gabriel Judde (JG)

XenTech, 91000, Evry, France.

Françoise Farace (F)

INSERM, U981 "Identification of Molecular Predictors and new Targets for Cancer Treatment", 94805, Villejuif, France. francoise.farace@gustaveroussy.fr.
Gustave Roussy, Université Paris-Saclay, "Circulating Tumor Cells" Translational Platform, CNRS UMS3655-INSERM US23 AMMICA, 94805, Villejuif, France. francoise.farace@gustaveroussy.fr.
ORCID: 0000-0001-8563-160X

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