TRIM28 promotes luminal cell plasticity in a mouse model of prostate cancer.
Ashutosh S YendeEmily C WilliamsAndrew PletcherAlexandra HelfandHelen IbeawuchiTanya M NorthPatricia S LathamAnelia HorvathMaho ShibataPublished in: Oncogene (2023)
The Tripartite motif-containing 28 (TRIM28) transcriptional cofactor is significantly upregulated in high-grade and metastatic prostate cancers. To study the role of TRIM28 in prostate cancer progression in vivo, we generated a genetically-engineered mouse model, combining prostate-specific inactivation of Trp53, Pten and Trim28. Trim28 inactivated NPp53T mice developed an inflammatory response and necrosis in prostate lumens. By conducting single-cell RNA sequencing, we found that NPp53T prostates had fewer luminal cells resembling proximal luminal lineage cells, which are cells with progenitor activity enriched in proximal prostates and prostate invagination tips in wild-type mice with analogous populations in human prostates. However, despite increased apoptosis and reduction of cells expressing proximal luminal cell markers, we found that NPp53T mouse prostates evolved and progressed to invasive prostate carcinoma with a shortened overall survival. Altogether, our findings suggest that TRIM28 promotes expression of proximal luminal cell markers in prostate tumor cells and provides insights into TRIM28 function in prostate tumor plasticity.
Keyphrases
- prostate cancer
- benign prostatic hyperplasia
- single cell
- cell cycle arrest
- induced apoptosis
- radical prostatectomy
- mouse model
- rna seq
- inflammatory response
- wild type
- high grade
- cell death
- pi k akt
- oxidative stress
- signaling pathway
- squamous cell carcinoma
- type diabetes
- low grade
- metabolic syndrome
- mesenchymal stem cells
- poor prognosis
- toll like receptor
- high fat diet induced
- skeletal muscle
- lipopolysaccharide induced
- heat shock protein
- free survival