Abstract 5804: Heterogeneity in androgen receptor and IL-1beta expression by prostate cancer cells in skeletal metastases
Authors: Worrede-Mahdi Asurayya A. , Diaz Melisa , Fatatis Alessandro 
Published: July 2017

Bone metastases are a prevalent complication of advanced prostate cancer (PCa). The current standard of care for advanced PCa patients is androgen deprivation therapy (ADT), which fails within approximately two years and patients progress to castration resistant prostate cancer (CRPC). CRPC presents with additional metastasis in soft tissues and is incurable. We have found that in PCa patients, bone metastases have heterogeneous Androgen Receptor (AR) expression, and that cells lacking AR are the only PCa cell type that secretes the cytokine Interleukin-1 beta (IL-1β). Furthermore, pre-clinical work in our lab has revealed the role for IL-1β in promoting bone colonization by AR+ PCa cells and generation of heterogeneous skeletal metastases. A significant barrier to studying tumor heterogeneity in PCa metastasis has been the lack of an animal model to study the interaction between multiple PCa phenotypes in the bone microenvironment. By engrafting a suspension containing both AR− and AR+ cells directly into the left cardiac ventricle of mice, our lab has developed an in vivo model that allows us to study the progression of both AR− and AR+ cells in skeletal and soft tissue metastases. AR− and AR+ cells were genetically engineered to express two different Luciferase constructs (630 nm Red-shifted Luc and 540 nm Luc2 respectively) thereby allowing the progression of AR− and AR+ cells to be independently tracked and quantified. We used this model in combination with histological and radiographic analyses to assimilate the pathological features of our in vivo mixed AR+/AR− metastases to the human clinical scenario. Finally, we used castrated mice to determine whether IL-1β secreting PCa cells could support the growth and survival of IL-1β–/AR+ cells in androgen deprived conditions.

Co-injection of AR− (PC3-ML) and AR+ cells (LNCaP, VCaP, and 22Rv1) leads to increased establishment of soft tissue metastases as compared to injecting AR− cells alone. Unlike the metastases generated by PC3-ML cells alone, which show exclusively osteolytic activity, AR−/AR+ mixed metastases are both osteosclerotic and osteolytic, thereby recapitulating clinical pathology. Finally, preliminary results suggest that co-injection with IL-1β-secreting AR− cells enables the growth of androgen-dependent AR+ cells in castrated mice. This animal model of metastasis heterogeneity recapitulates human pathology and enables further interrogation of the mechanism by which IL-1β supports survival of AR+ cells and the potential role for AR− in evading AR-targeted therapy during castration resistant prostate cancer (CRPC).

Citation Format: Asurayya A. Worrede-Mahdi, Melisa Diaz, Alessandro Fatatis. Heterogeneity in androgen receptor and IL-1beta expression by prostate cancer cells in skeletal metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5804. doi:10.1158/1538-7445.AM2017-5804