Background: Androgen deprivation therapy (ADT), or chemical castration, is the first-line therapy for prostate cancer; however, resistance leaves few treatment options. Prostatic tumor-associated macrophages (TAMs) have been shown to promote prostate cancer growth and are abundant in castration-resistant prostate cancer (CRPC), suggesting a role in promoting CRPC. We recently showed a tumor cell-intrinsic mechanism by which RON promotes CRPC. Given previous reports that RON alters prostate cancer cell chemokine production and RON-overexpressing tumors alter macrophage function, we hypothesized that a macrophage-dependent mechanism regulated by tumor cell intrinsic RON also promotes CRPC.Methods: Using RON-modulated genetically engineered mouse models (GEMMs) and GEMM-derived cell lines and co-cultures with bone marrow-derived macrophages, we show functional and molecular characteristics of signaling pathways in supporting CRPC. Further, we used an unbiased phosphokinase array to identify pathway interactions regulated by RON. Finally, using human prostate cancer cell lines and prostate cancer patient data sets, we show the relevance of our findings to human prostate cancer. Results: Studies herein show that macrophages recruited into the prostate tumor microenvironment (TME) serve as a source for Gas6 secretion which serves to further enhance RON and Axl receptor activation in prostate tumor cells thereby driving CRPC. Further, we show targeting RON and macrophages in a murine model promotes CRPC sensitization to ADT. Conclusions: We discovered a novel role for the RON receptor in prostate cancer cells in promoting CRPC through the recruitment of macrophages into the prostate TME. Macrophage-targeting agents in combination with RON/Axl inhibition are likely to provide clinical benefits for patients with CRPC.
RON is a receptor tyrosine kinase (RTK) of the MET receptor family that is canonically involved in mediating growth and inflammatory signaling. RON is expressed at low levels in a variety of tissues, but its overexpression and activation have been associated with malignancies in multiple tissue types and worse patient outcomes. RON and its ligand HGFL demonstrate cross-talk with other growth receptors and, consequentially, positions RON at the intersection of numerous tumorigenic signaling programs. For this reason, RON is an attractive therapeutic target in cancer research. A better understanding of homeostatic and oncogenic RON activity serves to enhance clinical insights in treating RON-expressing cancers.
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.
Background: Aberrant RON signaling is present in numerous cancers including breast cancer. Evidence suggests that the ligand, hepatocyte growth factor-like (HGFL), is also overexpressed in breast cancer. RON (MST1R) and HGFL (MST1) genes are located on human chromosome 3 and mouse chromosome 9 respectively and are found near each other in both species. Based on co-expression patterns, we posited that RON and HGFL are co-regulated and that coordinate upregulation drives aggressive tumorigenesis. Methods: Mouse models were used to establish the functional significance of RON and HGFL co-overexpression on the activation of tumor cells and tumor-associated macrophages in breast cancer. TCGA and METABRIC gene expression and alteration data were used to query the relationships between MST1R and MST1 in breast cancer. Results: In tumor models, physiologic sources of HGFL modestly improve Arginase-1+ (M2) macrophage recruitment to the tumor proper. Tumor-cell produced HGFL functions in autocrine to sustain tumor cell RON activation and MAPK-dependent secretion of chemotactic factors and in paracrine to activate RON on macrophages and to promote breast cancer stem cell self-renewal. In silico analyses support that RON and HGFL are co-expressed across virtually all cancer types including breast cancer and that common genomic alterations do not appear to be drivers of RON/HGFL co-overexpression. Conclusions: Co-overexpression of RON and HGFL in breast cancer cells (augmented by physiologic sources of HGFL) promotes tumorigenesis through autocrine-mediated RON activation/RON-dependent secretome changes and paracrine activation of macrophage RON to promote breast cancer stem cell self-renewal.
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