Reproducible preclinical models of androgen receptor driven human prostate cancer bone metastasis.

Preclinical models recapitulating the metastatic phenotypes are essential for developing the next-generation therapies for metastatic prostate cancer (mPC). We aimed to establish a cohort of clinically relevant mPC models, particularly androgen receptor positive (AR+) bone metastasis models, from LuCaP patient-derived xenografts (PDX) that reflect the heterogeneity and complexity of mPC.

PDX tumors were dissociated into single cells, modified to express luciferase, and were inoculated into NSG mice via intracardiac injection. The progression of metastases was monitored by bioluminescent imaging. Histological phenotypes of metastases were characterized by immunohistochemistry and immunofluorescence staining. Castration responses were further investigated in two AR-positive models.

Our PDX-derived metastasis (PDM) model collection comprises three AR+ adenocarcinomas (ARPC) and one AR- neuroendocrine carcinoma (NEPC). All ARPC models developed bone metastases with either an osteoblastic, osteolytic, or mixed phenotype, while the NEPC model mainly developed brain metastasis. Different mechanisms of castration resistance were observed in two AR+ PDM models with distinct genotypes, such as combined loss of TP53 and RB1 in one model and expression of AR splice variant 7 (AR-V7) expression in another model. Intriguingly, the castration-resistant tumors displayed inter- and intra-tumor as well as organ-specific heterogeneity in lineage specification.

Genetically diverse PDM models provide a clinically relevant system for biomarker identification and personalized medicine in metastatic castration-resistant prostate cancer.

The Prostate. 2024 May 06 [Epub ahead of print]

JuanJuan Yin, Asha Daryanani, Fan Lu, Anson T Ku, John R Bright, Aian Neil S Alilin, Joel Bowman, Ross Lake, Chennan Li, Tri M Truong, Joseph D Twohig, Elahe A Mostaghel, Masaki Ishikawa, Mark Simpson, Shana Y Trostel, Eva Corey, Adam G Sowalsky, Kathleen Kelly

Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, Maryland, USA., Department of Pharmacology, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China., Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, Maryland, USA., Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA., Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA., Pathology and Laboratory Medicine, Perelman School of Medicine, Philadelphia, Pennsylvania, USA., Department of Urology, University of Washington, Seattle, Washington, USA.