An FEV-Associated Metastasis-Initiating-Like State Linked to Tumor Cell Plasticity and Immune Niche Remodeling in Prostate Cancer

Prostate cancer exhibits dynamic changes in malignant cell states, leading to metastasis, but the mechanisms behind this progression are not fully understood. To investigate, researchers integrated various data types, including single-cell and bulk transcriptomics, epigenomics, and experimental findings. This analysis revealed a distinct intermediate state, dubbed the metastasis-initiating-like (MIC-like) state, characterized by increased copy-number alterations, stemness, proliferation, MYC activity, and the closest transcriptional similarity to metastatic tumor cells.

The study further identified FEV as a key regulator linked to the MIC-like state, with similar transcriptional patterns and regulon activity. FEV is associated with a hybrid epithelial-mesenchymal phenotype, which is disrupted upon its perturbation. This disruption results in reduced epithelial and mesenchymal features, as well as impaired prostate cancer cell migration and invasion.

Additionally, FEV is linked to diminished cytotoxicity and interferon responses in the tumor microenvironment, through the regulation of MIF-family genes.

Beyond its intrinsic tumor-related roles, FEV demonstrates a reciprocal association with androgen signaling, and its expression patterns vary across different treatment response groups. These findings highlight FEV's potential relevance in therapeutic contexts, shedding light on its role in tumor cell plasticity and immune niche remodeling in prostate cancer.