Although early prostate cancer depends on the androgen receptor 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 name PIP4K2A) in the prostate epithelium. We report the development of a basal cell–specific genetically engineered mouse model targeting Pip4k2a alone or in combination with the tumor suppressor phosphatase and tensin homolog (Pten). PI5P4Kα is enriched in basal cells, and no major histopathologic changes were detectable following gene deletion. Notably, the combined loss of Pip4k2a slowed the development of Pten mutant mouse prostatic intraepithelial neoplasia. Through the inclusion of a lineage tracing reporter, we utilize single-cell RNA sequencing to evaluate changes resulting from in vivo downregulation of Pip4k2a and characterize cell populations influenced in the established Probasin-Cre– and cytokeratin 5-Cre–driven genetically engineered mouse model. Transcriptomic pathway analysis points toward the disruption of lipid metabolism as a mechanism for reduced tumor progression. This was functionally supported by shifts of carnitine lipids in LNCaP prostate cancer cells treated with siPIP4K2A. Overall, these data nominate PI5P4Kα as a target for PTEN mutant prostate cancer.

Implications: PI5P4Kα is enriched in prostate basal cells, and its targeted loss slows the progression of a model of advanced prostate cancer.

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©2024 The Authors; Published by the American Association for Cancer Research
2024
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License .
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Supplementary data

Supplementary Table S1

Table S1. Summary of genetically engineered mouse models (GEMMs)

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Supplementary Table S2

Table S2. Antibodies and reagents used

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Supplementary Table S3

Table S3. Crowley et al. markers for scRNA-Seq module scores

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Supplementary Table S4

Table S4. GSEA pathways from Fig. 6

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Supplementary Table S5

Table S5. Metabolomics summary

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Supplementary Figure S1

Figure S1. PIP4K2A expression in human scRNA-Seq dataset.

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Supplementary Figure S2

Figure S2. PI5P4Kα expression enriched in basal compartment.

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Supplementary Figure S3

Figure S3. Selected cell scRNA-Seq evaluation of prostate GEMMs.

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Supplementary Figure S4

Figure S4. Top ten differentially expressed genes in scRNA-Seq clusters.

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Supplementary Figure S5

Figure S5. scRNA-Seq comparison with atlas datasets.

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Supplementary Figure S6

Figure S6. Prostate morphology resulting from genomic loss of Pip4k2b isoform.

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Supplementary Figure S7

Figure S7. Immunohistochemical staining of CK5-PipPten model.

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Supplementary Figure S8

Figure S8. Differentially abundant pathways and metabolites from targeting PIP4K2A.

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