Epithelial mesenchymal-like transition occurs in a subset of cells in castration resistant prostate cancer bone metastases

Abstract

TGFβ is a known driver of epithelial-mesenchymal transition (EMT) which is associated with tumor aggressiveness and metastasis. However, EMT has not been fully explored in clinical specimens of castration-resistant prostate cancer (CRPC) metastases. To assess EMT in CRPC, gene expression analysis was performed on 149 visceral and bone metastases from 62 CRPC patients and immunohistochemical analysis was performed on 185 CRPC bone and visceral metastases from 42 CRPC patients. In addition, to assess the potential of metastases to seed further metastases the mitochondrial genome was sequenced at different metastatic sites in one patient. TGFβ was increased in bone versus visceral metastases. While primarily cytoplasmic; nuclear and cytoplasmic Twist were significantly higher in bone than in visceral metastases. Slug and Zeb1 were unchanged, with the exception of nuclear Zeb1 being significantly higher in visceral metastases. Importantly, nuclear Twist, Slug, and Zeb1 were only present in a subset of epithelial cells that had an EMT-like phenotype. Underscoring the relevance of EMT-like cells, mitochondrial sequencing revealed that metastases could seed additional metastases in the same patient. In conclusion, while TGFβ expression and EMT-associated protein expression is present in a considerable number of CRPC visceral and bone metastases, nuclear Twist, Slug, and Zeb1 localization and an EMT-like phenotype (elongated nuclei and cytoplasmic compartment) was only present in a small subset of CRPC bone metastases. Mitochondrial sequencing from different metastases in a CRPC patient provided evidence for the seeding of metastases from previously established metastases, highlighting the biological relevance of EMT-like behavior in CRPC metastases.

Skp2 deficiency restricts the progression and stem cell features of castration-resistant prostate cancer by destabilizing Twist

“…A recent gene expression analysis of CRPC tissues revealed a positive correlation between Twist expression and CRPC metastases. 23 Studies with TRAMP mice showed increased Twist expression in prostate tumors and its overexpression is associated with disease progression. 20 , 24 To further study the crosstalk between Skp2 and Twist as well as their requirements in the development and progression of CRPC.…”

Dual strands of pre-miR-150 (miR-150-5p and miR-150-3p) act as antitumor miRNAs targeting SPOCK1 in naïve and castration-resistant prostate cancer

“…Transforming growth factor β (TGFβ) is a pivotal player that induces EMT in cancer cells (40). Increased expression of TGFβ and EMT-related proteins has been observed in CRPC bone metastasis (41). Interestingly, expression of SPOCK1 is elevated by TGFβ treatment in lung cancer cells, suggesting that SPOCK1 mediates downstream TGFβ signaling (33).…”

Inhibition of ERG Activity in Patient-derived Prostate Cancer Xenografts by YK-4-279

“…Additionally, through IHC, tumors were evaluated from YK-4-279-treated and untreated animals for the known EMT transcription factors Twist and Zeb (Figures 9 and 10), but found no difference in protein expression between treated and untreated groups. Further, nuclear staining for these EMT-associated transcription factors was only observed in a subset of cells within each tumor (Figures 9 and 10) (22). Interestingly, in the top 20 genes up-regulated in the PDX tumors after YK-4-279 treatment (Figure 8), a number of genes associated with the mineralocorticoid receptor (MR) were identified.…”