Development and Characterization of a Spontaneously Metastatic Patient-Derived Xenograft Model of Human Prostate Cancer.
Tobias LangeSu Jung Oh-HohenhorstSimon A JoosseKlaus PantelOliver HahnTobias GosauSergey A DyshlovoyJasmin WellbrockSusanne FeldhausHanna MaarRenate GehrckeMartina KluthRonald SimonThorsten SchlommHartwig HulandUdo SchumacherPublished in: Scientific reports (2018)
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.
Keyphrases
- prostate cancer
- radical prostatectomy
- copy number
- squamous cell carcinoma
- small cell lung cancer
- high fat diet induced
- bone marrow
- single cell
- mitochondrial dna
- mesenchymal stem cells
- cell proliferation
- minimally invasive
- cell therapy
- dna methylation
- machine learning
- adipose tissue
- magnetic resonance
- case report
- type diabetes
- multiple sclerosis
- gene expression
- computed tomography
- pet ct
- pulmonary hypertension
- rna seq
- electronic health record
- pet imaging
- artificial intelligence
- umbilical cord
- induced pluripotent stem cells
- skeletal muscle
- cerebral ischemia