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

被引:57
|
作者
Faugeroux, Vincent [1 ,2 ]
Pailler, Emma [1 ,2 ]
Oulhen, Marianne [2 ]
Deas, Olivier [3 ]
Brulle-Soumare, Laura [3 ]
Hervieu, Celine [1 ,2 ]
Marty, Virginie [4 ]
Alexandrova, Kamelia [5 ]
Andree, Kiki C. [6 ]
Stoecklein, Nikolas H. [7 ]
Tramalloni, Dominique [5 ]
Cairo, Stefano [3 ]
NgoCamus, Maud [8 ]
Nicotra, Claudio [8 ]
Terstappen, Leon W. M. M. [6 ]
Manaresi, Nicolo [9 ]
Lapierre, Valerie [5 ]
Fizazi, Karim [1 ,8 ]
Scoazec, Jean-Yves [4 ]
Loriot, Yohann [8 ]
Judde, Jean-Gabriel [3 ]
Farace, Francoise [1 ,2 ]
机构
[1] INSERM, U981 Identificat Mol Predictors & New Targets Can, F-94805 Villejuif, France
[2] Univ Paris Saclay, Gustave Roussy, Circulating Tumor Cells Translat Platform, CNRS UMS3655 INSERM US23 AMMICA, F-94805 Villejuif, France
[3] XenTech, F-91000 Evry, France
[4] Univ Paris Saclay, Gustave Roussy, Expt & Translat Pathol Platform, CNRS UMS3655 INSERM US23 AMMICA, F-94805 Villejuif, France
[5] Univ Paris Saclay, Gustave Roussy, Dept Cell Therapy, F-94805 Villejuif, France
[6] Univ Twente, Med Cell Biophys Grp, Tech Med Ctr, Fac Sci & Technol, NL-7522 NB Enschede, Netherlands
[7] Heinrich Heine Univ Dusseldorf, Dept Gen Visceral & Pediat Surg, Fac Med, Univ Hosp, Dusseldorf, Germany
[8] Univ Paris Saclay, Gustave Roussy, Dept Canc Med, F-94805 Villejuif, France
[9] Menarini Silicon Biosyst SpA, I-40013 Bologna, Italy
关键词
BREAST-CANCER PATIENTS; DIAGNOSTIC LEUKAPHERESIS; LINEAGE PLASTICITY; DOCETAXEL; SURVIVAL; IDENTIFICATION; ESTABLISHMENT; MITOXANTRONE; METASTASIS; PREDNISONE;
D O I
10.1038/s41467-020-15426-2
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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. Better tumor models are needed for the neuroendocrine subtype of castration resistant prostate cancer (CRPC-NE). Here, the authors develop patient-derived model from circulating tumor cells of a CRPC-NE patient, and provide insights on the sequential acquisition of driver gene mutations promoting NE transdifferentiation.
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页数:16
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