# Extracellular vesicle-mediated transmission of circPDLIM5 promotes lymphatic metastasis in prostate cancer

## TL;DR

This study shows that a circular RNA called circPDLIM5, carried in extracellular vesicles from prostate cancer cells, promotes lymphatic metastasis independently of VEGF-C, offering a new therapeutic target.

## Contribution

The study identifies a VEGF-C-independent mechanism involving circPDLIM5 in extracellular vesicles that drives lymphatic metastasis in prostate cancer.

## Key findings

- Extracellular vesicles from prostate cancer cells promote lymphatic metastasis without VEGF-C.
- circPDLIM5 in these vesicles interacts with Yin Yang 1 to enhance lymphatic vessel formation.
- EVs carrying circPDLIM5 are packaged via heterogeneous nuclear ribonucleoprotein A2B1.

## Abstract

For patients with prostate cancer (PCa), pelvic lymph node (LN) metastasis remains a major poor prognostic factor associated with cancer-specific mortality. VEGF-C is a major lymphangiogenic ligand that plays a vital role in LN metastasis in PCa. However, in some PCa caseswith LN metastasis,VEGF-C is not upregulated, indicating that some VEGF-C-independent mechanisms are essential for lymphangiogenesis.Herein, we confirmed that extracellular vesicles (EVs) derived from PCa cells could promote LN metastasis in PCa independent of VEGF-C. We identified an EV circular RNA, circPDLIM5, that could promote lymphangiogenesis and lymphatic metastasis in both PCa cell lines and mouse models. Mechanistically, the packaging of circPDLIM5 into EVs was regulated by heterogeneous nuclear ribonucleoprotein A2B1. Subsequently, EVs were transmitted to human lymphatic endothelial cells, and EVs carrying circPDLIM5 could then directly interact with the transcription factor Yin Yang 1 to enhance the expression of Prospero homeobox 1, which is crucial for the formation, differentiation, and maturation of lymphatic vessels. Our findingshighlight the importance of a molecular mechanism mediated by EVs carrying circPDLIM5that is involved in lymphangiogenesis and LN metastasis in PCa; as a result, EVscarrying circPDLIM5 may be an attractive therapeutic target for LN-metastatic PCa.

The online version contains supplementary material available at 10.1186/s13046-025-03443-2.