Abstract 762: Spatial transcriptomic characterization of uterine carcinosarcomas identifies MECOM as a tumor regulator

Abstract Uterine carcinosarcoma is an aggressive subtype of endometrial cancer associated with poor patient outcomes. Less is known about the molecular features of this heterogeneous cancer, which is characterized by both epithelial and mesenchymal components. Our study aimed to use spatial transcriptomics to provide insights into its tumor biology. Spatial transcriptomics was performed using the NanoString DSP’s GeoMx 1, 800 Cancer Transcriptome Atlas. We evaluated 7 primary tumors, 5 of which had paired lymph node metastases. Planned comparisons were as follows: epithelial vs mesenchymal; epithelial vs stromal; mesenchymal vs stromal; primary vs metastatic tumor. In primary tumor, there was differential expression of cell-cell adhesion genes and keratins (both higher in epithelial), and epithelial-mesenchymal transition (EMT) genes and collagens (both higher in mesenchymal). The stroma had multiple immune genes upregulated, including genes relating to macrophage function, cytokine binding, and complement activation. To further investigate the immune findings, immunohistochemistry (IHC) from 4 cases showed inconsistent immune cell differences between the carcinoma and sarcoma compartments. In 3 of the 4 cases, CD3 (T cell) cells were higher in the carcinoma than in the sarcoma, and 2 of the 4 cases showed higher CD206 (M2 macrophage) in the sarcoma than the carcinoma compartments. Few differences in gene expression were noted between the primary and metastatic tumors. MECOM and SOX17, two stem cell genes found to be associated with more aggressive ovarian cancers, were both upregulated in the epithelial compartment relative to the mesenchymal or stromal compartments on transcriptomics. To further elucidate MECOM’s role in uterine carcinosarcoma, we used in situ hybridization and confirmed differential MECOM RNA expression in the tumor compartments of two different uterine carcinosarcoma cases. This was paralleled by higher protein expression in the epithelial relative to the mesenchymal tumor compartments in 12 cases (IHC). Then, MECOM was knocked down in two uterine carcinosarcoma cell lines. While no differences in proliferation were noted, blocking MECOM led to lower expression of EMT-related proteins. These data suggest that MECOM may be linked to EMT characteristics within uterine carcinosarcoma. The immune characterization of uterine carcinosarcoma is likely complex given the inherent heterogeneity of these tumors, and should be further evaluated. Citation Format: Sanaa N. Borrego, Elizabeth Kertowidjojo, Yan Li, Agnes Bilecz, Bridget Rodig, Lucy Kelliher, Hilary Kenny, Ernst Lengyel, Katherine C. Kurnit. Spatial transcriptomic characterization of uterine carcinosarcomas identifies MECOM as a tumor regulator [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 762.