Spatial Transcriptomic Profiling Of Advanced Ovarian Clear Cell Carcinoma Reveals Intra-Tumor Heterogeneity In Epithelial-Mesenchymal Gradient

Intratumoral heterogeneity is intrinsically comprised of molecular alterations of tumor cells and extrinsically from interconnections with microenvironments. This study explores the spatial heterogeneity of ovarian clear cell carcinoma (OCCC), a rare cancer with significance to East Asian women. We profiled 21 tumors from matched ovarian and metastatic sites with spatial transcriptomic (ST) platforms including GeoMx and Visium CytAssist. Three subclusters of OCCC tumor cells enriched in oxidative phosphorylation, epithelial-mesenchymal transition, and inflammation pathways were identified with preferential geospatial localizations in tumor centers and invasive margins/tumor-stromal interfaces. These ST subclusters correlated with epithelial-mesenchymal gradients and prognostic features in larger cohorts. Single-cell ST in CosMx identified 9 cancer cell populations with organ-specific tropism. Trajectory analysis indicated a NEAT1-high subclone having founder characteristics, progressively dominating the metastatic niche, displaying mesenchymal traits. This founder feature correlated with clinical outcomes in PanCancer datasets. Our findings highlight the adaptive and context-specific interactions between cancer cells and microenvironments within spatial complexities.