Innate immunity and Nfkb pathway control prostate stem cell plasticity, reprogramming and tumor initiation

Prostate epithelium develops from multipotent stem cells (SCs) which are replaced in adult life by different lineage-restricted basal and luminal unipotent SCs that sustain the homeostasis in a regionalized manner. Deletion of Pten re-induces multipotency in basal cells (BC). However, the molecular mechanisms regulating cell plasticity and tumor initiation are poorly understood. Here, we showed that Pten deletion in BCs led to distinct cell fate reprograming and tumor initiation in a regionalized manner. In anterior and dorsal prostates, BCs were reprogrammed into a Hillock like state that progressed into a basal-luminal hybrid state, which further transitioned into a proximal-like luminal state before progressing to tumorigenesis. In the ventral prostate, BC expressing Nkx3.1 gave rise to distal-like luminal state that are less plastic and progress more slowly to tumorigenesis. Single-cell sequencing and ATAC-seq analysis showed that the reprograming into hillock and proximal states induced activation of the innate immunity pathway during the cellular reprograming and tumor formation. Targeting Il-1, JAK/STAT and Nfkb inhibits Pten-induced cell plasticity and oncogenic reprograming, opening new opportunities in the prevention and treatment of prostate cancer. As Rapamycin treatment strongly inhibits the activation of BC multipotency and the initiation of prostate tumorigenesis, we performed bulk-RNAseq in BCs 3 weeks following Pten deletion and PI3K activation to further investigate the mechanisms that lead to the cell fate changes