Abstract 4722: Inactivation of neogenin promotes castration resistance and bone metastasis in prostate cancer models

Increasing evidence suggests that exposure to new generation agents targeting the AR promotes the emergence of castration-resistant stem-like clones ultimately leading to treatment failure. In order to develop improved therapies for castration-resistant prostate cancer (CRPC), it is important to understand the origin and biology of these stem-like clones. We have observed significantly diminished levels of Neogenin (encoded by NEO1) in CRPC. Neogenin functions as a neuronal guidance receptor but has also been implicated in epithelial branching morphogenesis and is homologous to DCC, which functions as a suppressor of tumor progression in breast and colorectal cancer. We found that silencing of neogenin induces androgen receptor (AR) dependent prostate cancer cells to undergo an epithelial to mesenchymal transition (EMT) and acquire neuroendocrine (NE) differentiation features. In addition, the neogenin-silenced cells expressed high levels of the stem cell markers β4 integrin and CD44 and formed rapidly growing tumor spheres in vitro. Intriguingly, these cells had become castration resistant due to loss of AR expression and were able to efficiently colonize the bone upon intracardiac injection in immunodeficient mice. Genomic and molecular pathology studies indicated that NEO1 expression is lost in CRPC and NEPC. To examine the relationship between the acquisition of the castration resistant phenotype and loss of neogenin, we have generated a series of casodex- and enzalutamide-resistant clones from LNCaP cells. Interestingly, we observed that a significant fraction of these clones have lost expression of neogenin and acquired expression of the β4 integrin and are highly metastatic in immunodeficient mice, similar to the characteristics of CRPC observed in the clinic. To validate these results, we sought to identify a population of β4-positive cells in the peripheral blood of patients with CRPC. By using immunofluorescent staining and FACS analysis, we were able to identify β4-positive circulating tumor cells (CTCs) from the peripheral blood of CRPC patients. These cells were not detected in the blood of healthy normal donors but their numbers increased with disease progression. These findings identify a novel tumor progression pathway that is likely to operate in at least a fraction of CRPC cases. Citation Format: Goutam Chakraborty, Mayur Gadiya, Myriam Kossai, Dong Gao, Weijing Su, Hua Gao, Yu Chen, Howard I. Scher, Mark A. Rubin, Filippo Giancotti. Inactivation of neogenin promotes castration resistance and bone metastasis in prostate cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4722. doi:10.1158/1538-7445.AM2015-4722