Loss of PI5P4Kα slows the progression of aPtenmutant basal cell model of prostate cancer

Abstract

ABSTRACTWhile early prostate cancer (PCa) depends on the androgen receptor (AR) signaling pathway, which is predominant in luminal cells, there is much to be understood about the contribution of epithelial basal cells in cancer progression. Herein, we observe cell-type specific differences in the importance of the metabolic enzyme phosphatidylinositol 5-phosphate 4-kinase alpha (PI5P4Kα; gene namePIP4K2A) in the prostate epithelium. We report the development of a basal-cell-specific genetically engineered mouse model (GEMM) targetingPip4k2aalone or in combination with the tumor suppressor phosphatase and tensin homolog (Pten). PI5P4Kα is enriched in basal cells, and no major histopathological changes were detectable following gene deletion. Notably, the combined loss ofPip4k2aslowed the development ofPtenmutant mouse prostatic intraepithelial neoplasia (mPIN). Through the inclusion of a lineage tracing reporter, we utilize single-cell RNA sequencing to evaluate changes resulting fromin vivodownregulation ofPip4k2aand characterize cell populations influenced in the established Probasin-Cre and Cytokeratin 5 (CK5)- Cre driven GEMMs. Transcriptomic pathway analysis points towards the disruption of lipid metabolism as a mechanism for reduced tumor progression. This was functionally supported by shifts of carnitine lipids in LNCaP PCa cells treated withsiPIP4K2A. Overall, these data nominate PI5P4Kα as a target for PTEN mutant PCa.One Sentence SummaryLoss of PI5P4Kα slows cancer progression in prostate basal cells.