Project Summary/Abstract: There is a critical need to understand the pathogenesis of aggressive vs indolent prostate cancer. The combination of PTEN loss and MYC copy number gain predicts poor outcome in prostate cancer. Moreover, PTEN loss, even in low grade lesions, can indicate the presence of high grade aggressive prostate cancer. We found a synergistic interaction in driving aggressive prostatic adenocarcinoma by combining Pten loss with MYC overexpression in a mouse model (BMPC mice). However, the molecular mechanisms by which MYC and PTEN cooperate in driving aggressive disease are not known. We hypothesize that the combination stimulates a cell non-autonomous immune evasion mechanism through recruitment of immunosuppressive myeloid cells and cancer associated fibroblasts. We additionally hypothesize that these microenvironmental alterations accompanying progression to aggressive cancer with PTEN loss may have already been conditioned in PIA lesions within the proving ground from which these neoplastic cells initially emerged. These hypotheses are based on strong preliminary data and prior reports indicating that: i) the chemokine Cxcl5 is upregulated upon Pten deletion in prostate cancer precursors with high aggressive potential (BMPC PIN), and are associated with recruitment of polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs) and with increased M2 macrophages in BMPC invasive cancers; ii) these increases in myeloid cells in BMPC cancers parallel observations of increased M2 macrophages in high grade human prostate cancer and in association with PTEN loss; iii) aggressive human prostate cancer lesions with PTEN loss and in BMPC animals often harbor a reactive stroma, which is correlated with FAP expression, and which has been implicated as a driver of immunosuppression and cancer cell invasion; and iv) expression of CXCL5, and of FAP in the stroma, is associated with a subset of PIA lesions, suggesting that these features may already be conditioned in the PIA proving ground and reawakened during progression to aggressive disease with PTEN loss. In Aim 1, we hypothesize that Pten loss in BMPC PIN precursors leads to induction of the chemokine Cxcl5, which recruit PMN-MDSC and M2 macrophages to engender an immunosuppressive phenotype. In our preliminary data, we observed an association with FAP-positive reactive stroma in the vicinity of PTEN-lost human prostate cancer. Furthermore, FAP was upregulated in aggressive cancers from BMPC mice. In Aim 2, we will determine the role of reactive stroma and FAP in mediating immune evasion and aggressive prostate cancer in BMPC mice. In Aim 3, we hypothesize that the types of changes seen with PTEN loss, including FAP activation and CXCL5 upregulation, and myeloid cell infiltration, were already conditioned to occur during “graduation” of the neoplastic cells from the PIA proving ground. Thus, we will define the epithelial and microenvironmental alterations associated with PTEN loss in ...