TRIM28 promotes luminal cell plasticity in a mouse model of prostate cancer

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 inactiva...

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Bibliographic Details
Published in:Oncogene 2023-04, Vol.42 (17), p.1347-1359
Main Authors: Yende, Ashutosh S., Williams, Emily C., Pletcher, Andrew, Helfand, Alexandra, Ibeawuchi, Helen, North, Tanya M., Latham, Patricia S., Horvath, Anelia, Shibata, Maho
Format: Article
Language:English
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Animals
Apoptosis
Cell Biology
Cell Plasticity
Disease Models, Animal
Human Genetics
Humans
Inflammation
Internal Medicine
Male
Medicine
Medicine & Public Health
Metastases
Mice
Neoplastic Stem Cells - pathology
Oncology
Plasticity
Prostate - pathology
Prostate cancer
Prostate carcinoma
Prostatic Neoplasms - pathology
PTEN protein
Tripartite Motif-Containing Protein 28 - genetics
Tripartite Motif-Containing Protein 28 - metabolism
Tumor cells
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Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-023-02655-0