Abstract 6098: Analysis of the impact of ZEB1 expression on pathway enrichment and immune cell abundance in prostate cancer

Abstract Prostate cancer (PCa) reactivates a latent embryonic program called epithelial-mesenchymal transition during disease progression. The mesenchymal phenotype contributes to invasion, metastasis and therapy response variation. In this study, we characterize the downstream effects of ZEB1 expression based on cohort dichotomization of quartiles of expression comparing the 25% of tumors with high ZEB1 expression to the 75% of tumors with lower ZEB1 expression. Differential gene expression (DGE), gene set enrichment analysis (GSEA) and immune cell abundance prediction were accessed using PCa expression data from TCGA (n=488). ZEB1 high status based on gene expression was stratified based on ZEB1 expression values higher than the 3rd expression quartile value (n=122). Contingency analysis showed that PTEN loss is more frequent in the ZEB1 high group (Chi-square, p=0.0005) which supports previously presented data from our group that showed an inverse correlation between ZEB1 and PTEN protein expression but showed no difference between the groups regarding presence of the TMPRSS2-ERG fusion. DGE showed that more than 13,000 genes are differentially expressed in the ZEB1 high group while GSEA showed that signaling pathways such as HALLMARK TGF BETA, HALLMARK IL2 STAT5, HALLMARK INFLAMMATORY RESPONSE and HALLMARK NOTCH were upregulated in the ZEB1 high group compared to the low group. Yet inflammatory response related pathways were observed enriched in the ZEB1 high group, CIBERSORT analysis showed that effector immune cells such as CD8+ T cells and T helper cells (Holm-Sidak, p=000003 and p=0.000613, respectively) were enriched in the ZEB1 low group in comparison to the ZEB1 high group, which supports previous studies that suggest that ZEB1 cooperates with PTEN loss and TMPRSS2-ERG fusion to promote an immune evasive phenotype in PCa. Collectively, these findings demonstrate that gene expression changes associated with increased ZEB1 expression may involve clinically relevant pathways such as modulation of the tumor immune microenvironment and NOTCH-dependent tumor progression. Citation Format: Luiz Paulo Chaves, André Luiz Caliari, William Lautert-Dutra, Francisco Cesar Souza Silva, Camila Morais Melo, Fabiano Pinto Saggioro, Rodolfo Borges dos Reis, Jeremy Andrew Squire. Analysis of the impact of ZEB1 expression on pathway enrichment and immune cell abundance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6098.