Doppel as an early‐stage biomarker promoting EMT and dissemination in ovarian cancers

TL;DR

Doppel, a protein normally found in male testes, is a promising early biomarker for ovarian cancer that helps detect cancer and promote its spread.

Contribution

Doppel is shown to be a specific and sensitive biomarker for early-stage ovarian cancer and is linked to cancer progression through epithelial-mesenchymal transition.

Findings

Doppel levels in serum and ascites can detect ovarian cancer with high sensitivity and specificity.

Doppel induces epithelial–mesenchymal transition and correlates with circulating tumor cell dissemination.

Doppel is expressed in most epithelial ovarian cancer subtypes but not in clear cell OC.

Abstract

Detecting ovarian cancer (OC) early using existing biomarkers, for example, cancer antigen 125 (CA125), is challenging due to its ubiquitous expression in many tissues. Doppel, a prion‐like protein, expresses in the male reproductive organ but is absent in female reproductive systems and healthy tissues, but plays an important role in neo‐angiogenesis. Here, we have shown two platforms, soluble Doppel in sera/ascites and Doppel expressed in circulating tumor cells (Dpl+CTC) in the whole blood, to detect subsets of epithelial OC (EOC). Increased levels of Doppel in the sera of OC patients, in three different cohorts, confirm Doppel as an OC‐specific biomarker. Serum Doppel levels can distinguish OC with high sensitivity and specificity (sensitivity = 0.91 and specificity = 0.89) and can also detect early‐stage HGSOCs (FIGO stages I and II) from non‐cancerous conditions with high sensitivity and specificity (sensitivity = 0.94 and specificity = 0.83). Moreover, significantly higher Doppel expression is observed in all EOC subtypes except clear cell OC. Stratifying the EOCs based on Doppel levels, we categorized them into Doppel‐high (Dplhi) and Doppel‐low (Dpllow) groups. Using ascites‐derived organoids, made from Dplhi and Dpllow patients, we identify that Doppel induces epithelial–mesenchymal transition (EMT). Doppel levels in the sera/ascites correlate with the changes in Dpl+CTC number in whole blood, highlighting the association of Doppel‐induced EMT with CTC dissemination in the circulation. Thus, Doppel‐based detection of EOC subtypes could be a promising platform as a clinical biomarker and link the Doppel axis with OC dissemination.

What's new?

Existing biomarkers for ovarian cancer (OC) lack the sensitivity and specificity needed to consistently distinguish the malignancy from non‐ovarian influences and other cancers. Here, the authors explored the ability of the prion‐like protein Doppel, normally found in the male testes, to detect OC. Analyses show that Doppel is specifically expressed in OC tissues, being detectable in serum and ascites. In the latter, it further promotes epithelial–mesenchymal transition events, and in serum, its levels correlate with Doppel+ circulating tumor cell concentrations, suggesting that it facilitates OC dissemination. The findings highlight Doppel's potential as a diagnostic marker and driver of OC progression.

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