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

Vincent Faugeroux, Emma Pailler, Marianne Oulhen, Olivier Deas, Laura Brulle-Soumare, Céline Hervieu, Virginie Marty, Kamelia Alexandrova, Kiki C. Andree, Nikolas H. Stoecklein, Dominique Tramalloni, Stefano Cairo, Maud NgoCamus, Claudio Nicotra, Leon W. M. M. Terstappen, Nicolo Manaresi, Valérie Lapierre, Karim Fizazi, Jean-Yves Scoazec, Yohann Loriot (), Jean-Gabriel Judde and Françoise Farace ()
Additional contact information
Vincent Faugeroux: INSERM, U981 “Identification of Molecular Predictors and new Targets for Cancer Treatment”
Emma Pailler: INSERM, U981 “Identification of Molecular Predictors and new Targets for Cancer Treatment”
Marianne Oulhen: CNRS UMS3655—INSERM US23 AMMICA
Olivier Deas: XenTech
Laura Brulle-Soumare: XenTech
Céline Hervieu: INSERM, U981 “Identification of Molecular Predictors and new Targets for Cancer Treatment”
Virginie Marty: CNRS UMS3655–INSERM US23 AMMICA
Kamelia Alexandrova: Department of Cell Therapy
Kiki C. Andree: University of Twente
Nikolas H. Stoecklein: University Hospital of the Heinrich-Heine-University Düsseldorf
Dominique Tramalloni: Department of Cell Therapy
Stefano Cairo: XenTech
Maud NgoCamus: Department of Cancer Medicine
Claudio Nicotra: Department of Cancer Medicine
Leon W. M. M. Terstappen: University of Twente
Nicolo Manaresi: Menarini Silicon Biosystems S.p.A
Valérie Lapierre: Department of Cell Therapy
Karim Fizazi: INSERM, U981 “Identification of Molecular Predictors and new Targets for Cancer Treatment”
Jean-Yves Scoazec: CNRS UMS3655–INSERM US23 AMMICA
Yohann Loriot: Department of Cancer Medicine
Jean-Gabriel Judde: XenTech
Françoise Farace: INSERM, U981 “Identification of Molecular Predictors and new Targets for Cancer Treatment”

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15426-2

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