The Role of Non-Mutated Signaling Networks and Inflammatory Cytokines in the Initiation and Progression of Prostate Cancer

Prostate cancer is the most highly diagnosed, non-cutaneous cancer and second leading cause of cancer-related death in the United States. Despite this, the molecular determinants that drive prostate cancer initiation and progression are still poorly understood. Identifying signaling networks that are activated in prostate cancer and how these pathways interact is therefore fundamental to our understanding of prostate cancer. Using a dissociated prostate tissue model, we are able to investigate the role of specific genes in the regeneration and transformation of prostate tissues. This system allows for interrogation of both cell-autonomous genes as well as paracrine factors secreted by the surrounding microenvironment. Further, prostate epithelial tumors can be obtained from defined oncogenic combinations and the pathways and interactions between these oncogenes interrogated through a variety of ex vivo techniques. We used the dissociated prostate tissue system to develop an array of transformation states using defined sets of oncogenes. These tumors were then interrogated using phosphotyrosine enrichment combined with mass spectrometry analysis to identify key signaling nodes activated by specific oncogenic combinations. By defining the signaling networks that are activated by specific oncogenic combinations, we begin to identify common signaling nodes that can be targeted therapeutically. Whole genome sequencing studies have shown that prostate cancer exhibits a relatively low mutation frequency. We hypothesized that oncogenic transformation could therefore be driven by the over-expression of non-mutated proteins that would then activate specific oncogenic pathways leading to transformation. We interrogated the effects of increased expression of Src kinase and the androgen receptor, and identified that upon heightened co-expression of the non-mutated forms was sufficient to drive prostate transformation. We then interrogated the role of inflammatory cytokines and their ability to drive prostate cancer initiation and progression using interleukin-6 (IL6) and the related oncostatin-M (OSM) cytokines. Increased expression of either IL6 or OSM was sufficient to drive progression of PTEN-initiated lesions, indicating functional synergy. Further, increased expression of these cytokines was associated with an increase in activation of pathways downstream of these inflammatory cytokines. These data indicate that heightened expression of non-mutated genes can promote activation of pathways associated with oncogenesis and are sufficient to drive prostate epithelial transformation