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

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

  • Nat Commun. 2020 Apr 20;11(1):1884. doi: 10.1038/s41467-020-15426-2.
Vincent Faugeroux 1 2,  Emma Pailler  # 1 2,  Marianne Oulhen  # 2,  Olivier Deas  # 3,  Laura Brulle-Soumare 3,  Céline Hervieu 1 2,  Virginie Marty 4,  Kamelia Alexandrova 5,  Kiki C Andree 6,  Nikolas H Stoecklein 7,  Dominique Tramalloni 5,  Stefano Cairo 3,  Maud NgoCamus 8,  Claudio Nicotra 8,  Leon W M M Terstappen 6,  Nicolo Manaresi 9,  Valérie Lapierre 5,  Karim Fizazi 1 8,  Jean-Yves Scoazec 4,  Yohann Loriot 10,  Jean-Gabriel Judde 3,  Françoise Farace 11 12
Affiliations

Affiliations

  • 1 INSERM, U981 "Identification of Molecular Predictors and new Targets for Cancer Treatment", 94805, Villejuif, France.
  • 2 Gustave Roussy, Université Paris-Saclay, "Circulating Tumor Cells" Translational Platform, CNRS UMS3655-INSERM US23 AMMICA, 94805, Villejuif, France.
  • 3 XenTech, 91000, Evry, France.
  • 4 Gustave Roussy, Université Paris-Saclay, Experimental and Translational Pathology Platform, CNRS UMS3655-INSERM US23 AMMICA, 94805, Villejuif, France.
  • 5 Gustave Roussy, Université Paris-Saclay, Department of Cell Therapy, 94805, Villejuif, France.
  • 6 Medical Cell Biophysics Group, Technical Medical Centre, Faculty of Science and Technology, University of Twente, 7522 NB, Enschede, The Netherlands.
  • 7 Department of General, Visceral and Pediatric Surgery, Medical Faculty, University Hospital of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
  • 8 Gustave Roussy, Université Paris-Saclay, Department of Cancer Medicine, 94805, Villejuif, France.
  • 9 Menarini Silicon Biosystems S.p.A, 40013, Bologna, Italy.
  • 10 Gustave Roussy, Université Paris-Saclay, Department of Cancer Medicine, 94805, Villejuif, France. [email protected].
  • 11 INSERM, U981 "Identification of Molecular Predictors and new Targets for Cancer Treatment", 94805, Villejuif, France. [email protected].
  • 12 Gustave Roussy, Université Paris-Saclay, "Circulating Tumor Cells" Translational Platform, CNRS UMS3655-INSERM US23 AMMICA, 94805, Villejuif, France. [email protected].
  • # Contributed equally.
PMID: 32313004 DOI: 10.1038/s41467-020-15426-2
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.

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