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PRDM16 Regulates Prostate Cancer Cell Dormancy and Prevents Bone Metastatic Outgrowth

ABSTRACT: Understanding dormancy in prostate cancer (PCa) is challenging due to model availability. Here, using murine and human PCa cell lines, we generated a stress-induced model of dormancy in vitro and demonstrated that the phenotype could be sustained upon intrailiac artery delivery into the bone marrow microenvironment. RNA-Seq analysis revealed that the transcription factor PR domain containing 16 (PRDM16) was commonly upregulated in dormant PCa cells compared to controls. Further, bone marrow disseminated tumor PCa cells from primary orthotopic tumors were largely positive for PRDM16. Genetic ablation and forced ectopic expression supported a role for PRDM16 in maintaining PCa dormancy in vitro and in vivo. Clinically, PRDM16 negatively correlated with disease recurrence, and PRDM16 negatively correlated with the E2F cell cycle program in disseminated tumor cells derived from PCa patient bone marrow. Gene enrichment and characterization studies implicated PRDM16 as a regulator of metabolic and cell cycle pathways. ChIP-qPCR further revealed that PRDM16 binds upstream of the promoter of RB1, a potent repressor of E2F activity. Overall, this study developed a straightforward method for inducing cancer cell dormancy and applied this approach to find that PRDM16 governs an intrinsic dormancy program in PCa.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE307958 | GEO | 2025/09/17

REPOSITORIES: GEO

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Project description:The ability to interrogate circulating tumor cells (CTC) and disseminated tumor cells (DTC) is restricted by the small number detected and isolated (typically <10). We wanted to determine if a commercially available technology could provide a transcriptomic profile of a single prostate cancer (PCa) cell. We clonally selected and cultured a single passage of cell cycle synchronized C4-2B PCa cells. Ten sets of single, 5-, or 10-cells were isolated using a micromanipulator under direct visualization with an inverted microscope. Additionally, we analyzed 10 individual DTC isolated from each of 2 patients with metastatic PCa. We have shown that a transcriptomic profile can be obtained from a single cell using commercially available technology. As expected, fewer amplified genes are detected from a single-cell sample than from pooled cell samples, but this method can be used to obtain a transcriptomic profile from DTC isolated from the bone marrow of patients with PCa. Custom Agilent 44K whole human genome expression oligonucleotide microarrays were used to profile clonally selected and cultured single passage of cell cycle synchronized C4-2B PCa cells isolated using a micromanipulator under direct visualization with an inverted microscope into ten sets of single, 5-, or 10-cells. Single disseminated tumor cells were isolated from bone marrow (BM) samples of two advanced prostate cancer patients. Essentially, a two-step selection process was employed, in which anti-CD45 and anti-CD61 conjugated to immunomagnetic beads were used for negative selection, and anti-HEA was used for positive selection. Cells were then fluorescently stained for BerEP4, counter stained with RPE anti-CD45, and individually selected (10 single cells each per patient) under fluorescent light using a micropipette system for further analysis. RNA was amplified using the WT-Oviation one-direct system and hybridization against a common reference pool of prostate tumor cell lines. Data from C42B cell data and data from single cells isolated from the bone marrow of patients were normalized and analyzed separately.

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PRDM16 Regulates Prostate Cancer Cell Dormancy and Prevents Bone Metastatic Outgrowth

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