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

Author

Listed:
  • Vincent Faugeroux

    (INSERM, U981 “Identification of Molecular Predictors and new Targets for Cancer Treatment”
    CNRS UMS3655—INSERM US23 AMMICA)

  • Emma Pailler

    (INSERM, U981 “Identification of Molecular Predictors and new Targets for Cancer Treatment”
    CNRS UMS3655—INSERM US23 AMMICA)

  • 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”
    CNRS UMS3655—INSERM US23 AMMICA)

  • 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”
    Department of Cancer Medicine)

  • 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”
    CNRS UMS3655—INSERM US23 AMMICA)

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.

Suggested Citation

  • Vincent Faugeroux & Emma Pailler & Marianne Oulhen & Olivier Deas & Laura Brulle-Soumare & Céline Hervieu & Virginie Marty & Kamelia Alexandrova & Kiki C. Andree & Nikolas H. Stoecklein & Dominique Tr, 2020. "Genetic characterization of a unique neuroendocrine transdifferentiation prostate circulating tumor cell-derived eXplant model," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15426-2
    DOI: 10.1038/s41467-020-15426-2
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