A genome-wide CRISPR screen in human prostate cancer cells reveals drivers of macrophage-mediated cell killing and positions AR as a tumor-intrinsic immunomodulator.
Anniek ZaalbergEmma MinneeIsabel Mayayo-PeraltaKarianne SchuurmanSebastian GregoricchioThijs A van SchaikLiesbeth HoekmanDapei LiEva CoreyHans JanssenCor LieftinkStefan PrekovicMaarten AltelaarPeter S NelsonRoderick L BeijersbergenWilbert ZwartAndries BergmanPublished in: bioRxiv : the preprint server for biology (2023)
The crosstalk between prostate cancer (PCa) cells and the tumor microenvironment plays a pivotal role in disease progression and metastasis and could provide novel opportunities for patient treatment. Macrophages are the most abundant immune cells in the prostate tumor microenvironment (TME) and are capable of killing tumor cells. To identify genes in the tumor cells that are critical for macrophage-mediated killing, we performed a genome-wide co-culture CRISPR screen and identified AR, PRKCD, and multiple components of the NF-κB pathway as hits, whose expression in the tumor cell are essential for being targeted and killed by macrophages. These data position AR signaling as an immunomodulator, and confirmed by androgen-deprivation experiments, that rendered hormone-deprived tumor cells resistant to macrophage-mediated killing. Proteomic analyses showed a downregulation of oxidative phosphorylation in the PRKCD- and IKBKG-KO cells compared to the control, suggesting impaired mitochondrial function, which was confirmed by electron microscopy analyses. Furthermore, phosphoproteomic analyses revealed that all hits impaired ferroptosis signaling, which was validated transcriptionally using samples from a neoadjuvant clinical trial with the AR-inhibitor enzalutamide. Collectively, our data demonstrate that AR functions together with the PRKCD and the NF-κB pathway to evade macrophage-mediated killing. As hormonal intervention represents the mainstay therapy for treatment of prostate cancer patients, our findings may have direct implications and provide a plausible explanation for the clinically observed persistence of tumor cells despite androgen deprivation therapy.
Keyphrases
- genome wide
- prostate cancer
- dna methylation
- induced apoptosis
- signaling pathway
- clinical trial
- adipose tissue
- single cell
- radical prostatectomy
- cell cycle arrest
- cell therapy
- electronic health record
- high throughput
- type diabetes
- copy number
- crispr cas
- randomized controlled trial
- cell death
- nuclear factor
- endothelial cells
- lps induced
- benign prostatic hyperplasia
- stem cells
- big data
- cell proliferation
- cancer therapy
- pi k akt
- gene expression
- radiation therapy
- genome editing
- data analysis
- metabolic syndrome
- transcription factor
- endoplasmic reticulum stress
- open label
- induced pluripotent stem cells
- drug delivery
- insulin resistance
- immune response
- combination therapy
- study protocol
- replacement therapy