1. Investigating the Role of SNAI1 and ZEB1 Expression in Prostate Cancer Progression and Immune Modulation of the Tumor Microenvironment.
- Author
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Lautert-Dutra, William, Melo, Camila Morais, Chaves, Luiz Paulo, Sousa, Francisco Cesar, Crozier, Cheryl, Dion, Dan, Avante, Filipe S., Saggioro, Fabiano Pinto, dos Reis, Rodolfo Borges, Archangelo, Leticia Fröhlich, Bayani, Jane, and Squire, Jeremy A.
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RISK assessment , *FLOW cytometry , *CANCER relapse , *EPITHELIAL-mesenchymal transition , *T-test (Statistics) , *RESEARCH funding , *IMMUNOTHERAPY , *PROSTATE tumors , *TUMOR markers , *CANCER patients , *RETROSPECTIVE studies , *GENE expression , *BIOINFORMATICS , *LONGITUDINAL method , *KAPLAN-Meier estimator , *GENE expression profiling , *DATA analysis software , *DISEASE progression , *NEOVASCULARIZATION , *IMMUNE checkpoint proteins , *DISEASE risk factors - Abstract
Simple Summary: We evaluate the downstream effects of the Epithelial-to-Mesenchymal Transition (EMT) transcription factors, ZEB1 and SNAI1, and analyze their potential significance as biomarkers for increased aggressiveness and immune response in prostate cancer (PCa). We used two commercial expression profiling panels to examine a primary PCa cohort (n = 51) and identified changes in gene expression linked to downstream pathways associated with biochemical recurrence and increased clinical risk. Genes such as COL1A1, COL1A2, and COL3A1, which are implicated in the tumor microenvironment, and immune-related genes, such as THY1, IRF5, and HLA-DRA, exhibited significant expression level changes. Enrichment analysis identified pathways associated with angiogenesis, TGF-beta, EMT, and UV response in PCa progression. Confirmatory analyses conducted using public domain data demonstrated the downstream impacts of ZEB1 and SNAI1 on pathways and immune responses, highlighting their potential influence on immune modulation in PCa. Future treatment strategies aimed at modulating EMT may enhance immune cell infiltration toward an anti-tumorigenic phenotype. 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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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