Dissertation

Novel Roles for Ron Receptor Signaling as a Driver of Therapeutic Resistance in Prostate Cancer

Brown, Nicholas E

2018

Overview

Approximately 14% of all men will be diagnosed with prostate cancer. Not only is prostate cancer very prevalent, but as the second leading cause of cancer related deaths in men, it is also very deadly. Many of these deaths result from resistance to androgen deprivation therapy (ADT), defined as Castration Resistant Prostate Cancer (CRPC). The majority of men with CRPC die within 5 years of diagnosis, emphasizing the need for further research for novel CRPC therapeutics. Many prostate cancers become resistant to ADT through reactivation of the Androgen Receptor (AR). Within this dissertation, we demonstrate that the cell surface receptor Ron tyrosine kinase is important in activating AR in prostate cancer under conditions of androgen deprivation, leading to resistance to ADT. Previous studies established the Ron receptor and its ligand (HGFL) as critical players in prostate cancer, with Ron expression levels in prostate cancer correlating with disease severity and loss of Ron or HGFL in the Transgenic Adenocarcinoma of Mouse Prostate model of prostate cancer severely reducing primary tumor growth. These previous studies were critical in demonstrating the importance of Ron in prostate cancer, but had yet to address the potential role of Ron in regulating CRPC. We observed that Ron overexpression was sufficient to drive resistance to castration therapy by overexpressing Ron in androgen sensitive murine and human cell lines for allograft and xenograft models of CRPC. Prostate tumors derived from Ron overexpressing prostate cancer cells display elevated AR activation and require AR to provide growth in androgen depleted conditions. Further, Ron was shown to activate AR in an epithelial cell specific manner through activation of NF-κB and β-Catenin. As we further analyzed the consequences of Ron overexpression in prostate cancer, we discovered increased macrophage recruitment into Ron overexpressing tumors. We show that macrophage infiltration into Ron overexpressing tumors enhances AR, Ron, and Axl activation in prostate cancer cells through the secretion of Gas6, demonstrating a non-cell autonomous role for macrophages in promoting Ron mediated castration resistant growth. Excitingly, as we pursued the role of macrophage secreted Gas6 to drive growth of Ron overexpressing tumors we made the novel discovery that Gas6 binds to and induces activation of Ron. Discovery of this interaction has the potential to provide clarity to a number of questions that have remained unanswered regarding the role of Ron in the absence of HGFL. As we further investigated roles for Ron in prostate cancer we made the observation that Ron signaling is important for enhancing the effects of diet-induced obesity on prostate cancer. Obese patients have a higher incidence of developing aggressive metastatic prostate cancer compared to lean patients. Herein we provide evidence that adipocyte specific Ron signaling is essential for obesity to enhance prostate cancer growth and metastatic potential. Taken together, this work demonstrates several novel functions for the Ron receptor in driving prostate cancer and provides rationale for targeting this signaling pathway for the treatment of men with aggressive disease.

• Publisher: ProQuest Dissertations & Theses
• Subject: Biology / Immunology / Oncology
• ISBN: 9798557088909