Investigating the Role of SNAI1 and ZEB1 Expression in Prostate Cancer Progression and Immune Modulation of the Tumor Microenvironment.

Prostate cancer (PCa) is an immunologically cold tumor and the molecular processes that underlie this behavior are poorly understood. In this study, we investigated a primary cohort of intermediate-risk PCa (n = 51) using two NanoString profiling panels designed to study cancer progression and immune response. We identified differentially expressed genes (DEGs) and pathways associated with biochemical recurrence (BCR) and clinical risk. Confirmatory analysis was performed using the TCGA-PRAD cohort. Noteworthy DEGs included collagens such as COL1A1, COL1A2, and COL3A1. Changes in the distribution of collagens may influence the immune activity in the tumor microenvironment (TME). In addition, immune-related DEGs such as THY1, IRF5, and HLA-DRA were also identified. Enrichment analysis highlighted pathways such as those associated with angiogenesis, TGF-beta, UV response, and EMT. Among the 39 significant DEGs, 11 (28%) were identified as EMT target genes for ZEB1 using the Harmonizome database. Elevated ZEB1 expression correlated with reduced BCR risk. Immune landscape analysis revealed that ZEB1 was associated with increased immunosuppressive cell types in the TME, such as naïve B cells and M2 macrophages. Increased expression of both ZEB1 and SNAI1 was associated with elevated immune checkpoint expression. In the future, modulation of EMT could be beneficial for overcoming immunotherapy resistance in a cold tumor, such as PCa.

Epithelial-Mesenchymal Transition Signaling and Prostate Cancer Stem Cells: Emerging Biomarkers and Opportunities for Precision Therapeutics.

Prostate cancers may reactivate a latent embryonic program called the epithelial-mesenchymal transition (EMT) during the development of metastatic disease. Through EMT, tumors can develop a mesenchymal phenotype similar to cancer stem cell traits that contributes to metastasis and variation in therapeutic responses. Some of the recurrent somatic mutations of prostate cancer affect EMT driver genes and effector transcription factors that induce the chromatin- and androgen-dependent epigenetic alterations that characterize castrate-resistant prostate cancer (CRPC). EMT regulators in prostate cancer comprise transcription factors (SNAI1/2, ZEB1, TWIST1, and ETS), tumor suppressor genes (RB1, PTEN, and TP53), and post-transcriptional regulators (miRNAs) that under the selective pressures of antiandrogen therapy can develop an androgen-independent metastatic phenotype. In prostate cancer mouse models of EMT, Slug expression, as well as WNT/ß-Catenin and notch signaling pathways, have been shown to increase stemness potential. Recent single-cell transcriptomic studies also suggest that the stemness phenotype of advanced prostate cancer may be related to EMT. Other evidence correlates EMT and stemness with immune evasion, for example, activation of the polycomb repressor complex I, promoting EMT and stemness and cytokine secretion through RB1, TP53, and PRC1. These findings are helping clinical trials in CRPC that seek to understand how drugs and biomarkers related to the acquisition of EMT can improve drug response.

The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer.

Immunotherapy has improved patient survival in many types of cancer, but for prostate cancer, initial results with immunotherapy have been disappointing. Prostate cancer is considered an immunologically excluded or cold tumor, unable to generate an effective T-cell response against cancer cells. However, a small but significant percentage of patients do respond to immunotherapy, suggesting that some specific molecular subtypes of this tumor may have a better response to checkpoint inhibitors. Recent findings suggest that, in addition to their function as cancer genes, somatic mutations of PTEN, TP53, RB1, CDK12, and DNA repair, or specific activation of regulatory pathways, such as ETS or MYC, may also facilitate immune evasion of the host response against cancer. This review presents an update of recent discoveries about the role that the common somatic mutations can play in changing the tumor microenvironment and immune response against prostate cancer. We describe how detailed molecular genetic analyses of the tumor microenvironment of prostate cancer using mouse models and human tumors are providing new insights into the cell types and pathways mediating immune responses. These analyses are helping researchers to design drug combinations that are more likely to target the molecular and immunological pathways that underlie treatment failure.