Doppel as an early‐stage biomarker promoting <scp>EMT</scp> 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 (Dpl^hi) and Doppel-low (Dpl^low) groups. Using ascites-derived organoids, made from Dpl^hi and Dpl^low 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.