FOXA1 loss induces aggressive prostate cancer via unleashing basal/squamous de-differentiation and an immunosuppressive microenvironment [scRNA-seq]
FOXA1 is an epithelial transcription factor that is often found dysregulated in prostate cancer. Previous studies have reported both tumor-promoting and -inhibitory functions of FOXA1. However, a comprehensive analysis of FOXA1 in a physiological, immune-competent setting is still lacking. We here report a novel genetically engineered mouse model with Foxa1 KO in the Pten-null prostate epithelium for the study of FOXA1 loss within an immune-competent prostate tumor context. Here, we report Foxa1 loss induces prostate cancer lineage switch from a  luminal-like to a more aggressive basal/squamous-like phenotype, which is accompanied by  inflammatory and immunosuppressive cytokine signaling.  Mechanistically, in addition to inducing luminal genes, we found FOXA1 directly inhibits several basal/squamous, inflammatory, and cytokine genes, such that its loss unleashes their expression. Moreover, Foxa1 loss induces a striking remodeling of the prostate tumor immune microenvironment, leading to increased immunosuppressive myeloid accumulation and dysfunctional and spatially confined T cells. Altogether, we report critical roles for FOXA1 loss in inducing basal/squamous de-differentiation and an immunosuppressive microenvironment. Overall design: To investigate how Foxa1 loss regulates the prostate cancer transcriptome, epithelial cell reprogramming, and cellular diversity in prostate tumors, we performed scRNA-seq analysis of whole prostate tissues from age-matched PbCre4:Ptenf/f (P) and PbCre4:Ptenf/fFoxa1f/f (PF) mice. In addition, to phenotype immune populations in further detail, live CD45+ immune cells were sorted from age-matched P and PF mouse prostates for scRNA-seq analysis.