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

Vincent Faugeroux,Françoise Farace,Valérie Lapierre,Céline Hervieu,Karim Fizazi,Stefano Cairo,Nikolas H Stoecklein,Nicolò Manaresi ,Jean‐Yves Scoazec ,Claudio Nicotra,Jean-Gabriel Judde,Emma Pailler,Maud Ngo-Camus ,Marianne Oulhen,Laura Brullé-Soumaré ,Yohann Loriot,Dominique Tramalloni,Kamélia Alexandrova ,Olivier Déas ,Leon W.m.m Terstappen ,Virginie Marty,Kiki Andree

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.

Highlights

Transformation of castration-resistant prostate cancer (CRPC) into an aggressive neuroendocrine disease (CRPC-NE) represents a major clinical challenge and experimental models are lacking
Thirty milliliters blood samples were collected from 15 patients with advanced CRPC and the hematopoietic blood-cell depleted fraction was implanted in NOD. Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice (NSG) mice
Comprehensive analysis of primary tumor specimens, circulating tumor cells (CTCs) and CTC-derived eXplant (CDX)/CDX-derived cell line provided insights on the genetic basis of the tumorigenic activity of CTCs and enabled the reconstruction of the phylogenic evolution of tumorigenic CTCs. This genomic analysis suggests an order of acquisition of the key genetic drivers (i.e. TP53, PTEN, RB1) that govern transformation of CRPC into CRPC into an aggressive neuroendocrine phenotype (CRPC-NE) and show that this process requires tumorigenic CTCs harboring features of CRPC-NE

Summary

Introduction

Transformation of castration-resistant prostate cancer (CRPC) into an aggressive neuroendocrine disease (CRPC-NE) represents a major clinical challenge and experimental models are lacking. 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. CTCs are derived from the primary tumor and/or metastatic sites and can be found in the blood of a proportion of patients with prostate cancer depending on their clinical stage and the applied CTC detection technology. Comprehensive analysis of primary tumor (PT) specimens, CTCs, and the CDX and an in vitro CDX-derived cell line provide insight into the genetic basis of the tumorigenicy of CTCs and the stepwise transformation of CRPC into CRPC-NE in this unique experimental model

Methods

Results

Conclusion