Abstract 1243: RON receptor signaling enhances prostate cancer metastasis in Hi-Myc mice (2023)

Abstract Prostate cancer (PCa) is the second leading cause of cancer mortality among men globally. Death from PCa is typically due to the lack of effective treatments for advanced forms of prostate cancers including castration-resistant prostate cancer (CRPC) and metastatic prostate cancers (mPCa). Distantly metastasized cancers drop the 5-year survival rate from 98% to 30%. Understanding the intrinsic and extrinsic mechanisms that lead to the development of these advanced prostate cancers could improve treatment options. The RON receptor tyrosine kinase is a cell surface receptor, which is activated by growth factor ligands (HGFL or Gas6), which binding promotes several cancer phenotypes in various cancers including prostate cancer. Our laboratory has shown that RON is overexpressed in 86% of primary and 100% of metastatic human prostate cancers compared to normal prostate tissue. Additionally, we have shown that RON overexpression in the prostates of mice can induce Prostatic intraepithelial neoplasia (PIN) lesions, adenocarcinoma, and increases several cancer phenotypes including proliferation, cell survival, metastasis, and increased recruitment of tumor-associated macrophages. However, we have yet to explore the effect of RON on prostate cancer metastasis. We hypothesize that RON expression enhances metastasis by promoting an increase in the amount of disseminating prostate cancer cells. To test this hypothesis, the Hi-Myc mouse model has been employed. The MYC gene is one of the most dysregulated genes in prostate cancers and Myc expression has been detected in the early stages of prostate cancer development, PIN lesion, and all later stages of prostate cancer. Additionally, the Hi-Myc model is clinically relevant as prostate tumor development in this model is similar to that in humans in regard to progression from PIN lesions to adenocarcinoma. From the Hi-Myc model, we have generated two additional genetic modifications within prostate epithelial cells: 1) Hi-Myc mice with prostate-specific RON overexpression (OE) and 2) Hi-Myc mice with prostate-specific RON loss (ΔEpi). In this study we report that a lack of prostate RON expression diminishes adenocarcinoma development and metastasis within the Hi-Myc mouse model. Moreover, RON overexpression promotes the development of metastatic adenocarcinoma that was not observed in the prostates from Hi-Myc control mice. These studies suggest that RON expression supports the advancement of primary tumors to metastatic prostate cancer within the Hi-Myc mouse models. Therefore, future directions include determining the signaling pathways driven by RON that promotes this metastatic phenotype in both castration-sensitive and resistant tumors. Citation Format: Angelle D. Jones, Carissa Lester, Susan E. Waltz. RON receptor signaling enhances prostate cancer metastasis in Hi-Myc mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1243.