Project 1: Investigation of immune and stromal factors that promote prostate adenocarcinoma progression and castration response

Project Summary/Abstract Large scale sequencing efforts have comprehensively defined the genomic landscape of localized and metastatic prostate cancer, yielding an improved understanding of drivers of disease initiation and progression and greater insight into mechanisms of resistance to androgen receptor (AR) pathway inhibition. One limitation of this “tumor cell focused” genomic approach is a relative lack of insight into how the tumor microenvironment (TME) plays a role. However, recent advances in single cell sequencing technologies have opened the door to comprehensively examine tumor/microenvironment interactions with unprecedented precision. Our group has embraced this approach: initially to characterize epithelial/stromal interactions in the normal prostate, and now to delineate tumor cell/microenvironment interactions in genetically engineered mouse models (GEMMs) of prostate cancer. These studies reveal a striking level of complexity. We have not only defined previously unknown subpopulations of luminal epithelial and stromal cells in the normal prostate gland, but also we have shown how these populations change/evolve during progression to invasive disease and in response to AR pathway inhibition (i.e. castration). In addition, our preliminary data showing that depletion of tumor-infiltrating immune cells delays disease progression eliminates any doubt that these TME changes are secondary phenomena. Based on these findings, we hypothesize that the prostate TME (immune cells and stromal cells) plays a crucial role in disease progression. We will explore this hypothesis through three synergistic specific aims that: (i) address the mechanism by which tumor infiltrating immune cells enhance tumor progression; (ii) elucidate how changes in Wnt pathway signaling in prostate stroma promote invasion by tumor epithelium; and (iii) determine whether/how the response of prostate tumors to AR pathway inhibition is influenced by inhibition of AR in the surrounding TME cells. We have extensive experience with the GEMMs, tissue recombination assays and organoid culture that will be used to address these questions. We also have a strong track record of translating laboratory findings to the clinic, which will ensure the human relevance of our findings. Finally, this project is highly integrated with all other components of this program project: through collaborative interactions with the Shen lab in analyzing the transition to neuroendocrine disease, with the Abate-Shen lab in studies of Wnt pathway signaling in bone metastasis, with Core A for analysis of human tissue samples and with Core B for statistical support and data management.