Abstract
Here we describe the establishment and characterization of an AR+, PSMA+, ERG+, PTEN−/−, CHD1+/− patient-derived xenograft (PDX) model termed ‘C5’, which has been developed from a 60 years old patient suffering from castration-resistant prostate cancer (CRPC). The patient underwent radical prostatectomy, showed early tumor marker PSA recurrence and, one year after surgery, abiraterone resistance. Subcutaneous C5 tumors can be serially transplanted between mice and grow within ~90 days to 1.5–2 cm³ tumors in SCID Balb/c mice (take rate 100%), NOD-scid IL2Rgnull (NSG) mice (100%) and C57BL/6 pfp−/−/rag2−/− mice (66%). In contrast, no tumor growth is observed in female mice. C5 tumors can be cryopreserved and show the same growth characteristics in vivo afterwards. C5 tumor cells do not grow stably in vitro, neither under two- nor three-dimensional cell culture conditions. Upon serial transplantation, some C5 tumors spontaneously disseminated to distant sites with an observable trend towards higher metastatic cell loads in scid compared to NSG mice. Lung metastases could be verified by histology by means of anti-PSMA immunohistochemistry, exclusively demonstrating single disseminated tumor cells (DTCs) and micro-metastases. Upon surgical resection of the primary tumors, such pulmonary foci rarely grew out to multi-cellular metastatic colonies despite doubled overall survival span. In the brain and bone marrow, the metastatic cell load present at surgery even disappeared during the post-surgical period. We provide shallow whole genome sequencing and whole exome sequencing data of C5 tumors demonstrating the copy number aberration/ mutation status of this PCa model and proving genomic stability over several passages. Moreover, we analyzed genomic and transcriptomic alterations during metastatic progression achieved by serial transplantation. This study describes a novel PCa PDX model that enables future research on several aspects of metastatic PCa, particularly for the AR+ , ERG+ , PTEN−/− PCa subtype.
Highlights
Prostate cancer (PCa) is the most commonly diagnosed cancer in men in Western countries and the third leading cause of cancer-related deaths[1]
Most of the published patient-derived xenograft (PDX) studies were not intended to investigate the metastatic behavior of PCa10, and, if so, compared the metastatic potential of PDX tumors derived from different primary tumor foci of the same donor[23]
We analyzed metastatic progression during serial transplantation of a PDX model derived from one focus of one donor
Summary
Prostate cancer (PCa) is the most commonly diagnosed cancer in men in Western countries and the third leading cause of cancer-related deaths[1]. After initial remission upon ADT, many tumors return as castrate-resistant PCa (CRPC) that remain androgen-dependent, but are essentially untreatable and commonly develop distant metastases[4] Another unresolved problem is that some PCa patients experience a prolonged period (>5 years) after surgical resection of the primary tumor with no evidence of disease before the disease recurs at a metastatic, aggressive stage[5]. Orthotopic implantation has an approximately 70% take rate, but is technically challenging[11] and has been reported to develop lymph node, but not distant metastases[13] Despite these advances, the majority of published PCa PDX models was intended for the use in preclinical testing of the anti-tumor activity of novel drugs[10]. The novel PDX model was aimed to be characterized concerning genomic and transcriptomic changes during metastatic progression
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