Doppel As an Early‐stage Biomarker Promoting EMT and Dissemination in Ovarian Cancers

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.