# P-cadherin overexpression is associated with early transformation of the Fallopian tube epithelium and aggressiveness of tubo-ovarian high-grade serous carcinoma

## TL;DR

P-cadherin overexpression is linked to early cancer development in the Fallopian tube and aggressive behavior in a type of ovarian cancer with poor outcomes.

## Contribution

P-cadherin is identified as a novel biomarker for early transformation and aggressiveness in HR-proficient high-grade serous ovarian cancer.

## Key findings

- P-cadherin is overexpressed in pre-malignant and malignant Fallopian tube epithelium samples.
- High P-cadherin levels correlate with worse survival in HR-proficient HGSC without BRCA1/2 mutations.
- Reducing P-cadherin decreases hybrid E/M features in platinum-resistant cancer cells.

## Abstract

Tubo-ovarian high-grade serous carcinoma (HGSC) with proficient homologous recombination (HR) DNA repair (HRP) accounts for approximately 50% of cases and is associated with platinum-resistance and poor prognosis. We hypothesize that the acquisition of hybrid phenotypes displaying both epithelial and mesenchymal (E/M) features may be involved in the malignant transformation and tumour dissemination in this subgroup. Therefore, we analysed, by digital pathology, the expression and prognostic significance of 3 classic cadherins (E-cadherin, epithelial marker; N-cadherin, mesenchymal marker; and P-cadherin, candidate marker of hybrid E/M) in 577 formalin-fixed paraffin-embedded human samples representing the putative stepwise serous carcinogenesis in the Fallopian tube epithelium (FTE). We observed a non-canonical N-to-P-cadherin switch along the carcinogenic progression, with a statistically significant overexpression of P-cadherin in pre-malignant and malignant samples, compared to the control FTE. Interestingly, this overexpression was most pronounced in precursor lesions and HGSC cells from malignant ascites. Tumours with high P-cadherin expression were significantly associated with worse overall survival, especially in the subgroup without BRCA1/2 mutations. Transient P-cadherin knock-down resulted in in vitro significant reduction of functional hybrid E/M hallmarks, namely decreased anoikis resistance, reduced collective migration and invasion in a representative platinum-resistant HRP cell line. Taken together, our results suggest that P-cadherin overexpression is an early event in the serous carcinogenesis and may be involved in hybrid E/M activation in HRP-HGSC, further supporting this adhesion molecule as a promising biomarker for this poor prognostic subgroup.

The online version contains supplementary material available at 10.1007/s00428-025-04104-7.