ScRNA of the immune infiltrate of TRAMP-C1 allografts upon different androgen-deprivation therapeutic combinations
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE272999 | GEO | 2024/08/21
REPOSITORIES: GEO
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Project description:In immunosurveillance, bone-derived immune cells infiltrate the tumor and secrete inflammatory cytokines to destroy cancer cells. However, cancer cells have evolved mechanisms to usurp inflammatory cytokines to promote tumor progression. In particular, the inflammatory cytokine, interleukin-1 (IL-1), is elevated in prostate cancer (PCa) patient tissue and serum and promotes PCa bone metastasis. IL-1 also represses androgen receptor (AR) accumulation and activity in PCa cells, yet the cells remain viable; suggesting that IL-1 may also contribute to AR-targeted therapy resistance. Furthermore, IL-1 and AR protein levels negatively correlate in PCa tumor cells. Taken together, we hypothesize that IL-1 reprograms AR positive (AR+) PCa cells into AR negative (AR-) PCa cells that co-opt IL-1 signaling to ensure AR-independent survival in the inflammatory tumor microenvironment. Thus, we employed RNA sequencing to identify pathways that are modulated by IL-1 concomitant with IL-1-induced AR repression in PCa cells. Comparative analysis of sequencing data from the AR+ LNCaP PCa cell line versus the AR- PC3 PCa cell line reveals an IL-1-conferred gene suite in LNCaP cells that is constitutive in PC3 cells, and includes AR and AR target gene repression and the induction of prosurvival, lineage, and cancer stem cell genes. Bioinformatics analysis of the IL-1 regulated gene suite revealed that inflammatory and immune response pathways are primarily elicited; likely facilitating PCa cell survival in an inflammatory tumor microenvironment. Our data supports that IL-1 reprograms AR+ PCa cells to mimic AR- PCa gene expression patterns that favor AR-targeted treatment resistance and cell survival.
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Project description:Androgen receptor (AR) signaling remains the key therapeutic target in the management of hormone-naïve advanced prostate cancer (PCa) and castration-resistant PCa (CRPC). Recently, landmark molecular features have been reported for CRPC, including the expression of constitutively active AR variants that lack the ligand-binding domain. Besides their role in CRPC, AR variants lead to the expression of genes involved in tumor progression. However, little is known about the specificity of their mode of action compared with that of wild-type AR (AR-WT). We performed AR transcriptome analyses in an androgen-dependent PCa cell line as well as cross-analyses with publicly available RNA-seq dataset and established that transcriptional repression capacity that was marked for AR-WT was pathologically lost by AR variants. Functional enrichment analyses allowed us to associate AR-WT repressive function to a panel of genes involved in cell adhesion and epithelial-to-mesenchymal transition. So, we postulate that a less documented AR-WT normal function in prostate epithelial cells could be the repression of a panel of genes linked to cell plasticity, and that this repressive function could be pathologically abrogated by AR variants in PCA.
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