Abstract A046: Cell states and neighborhoods in distinct clinical stages of primary and metastatic esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is a highly lethal cancer of the upper gastrointestinal tract with rising incidence in western populations. To decipher EAC disease progression and therapeutic response, we performed multiomic analyses of a cohort of primary and metastatic EAC tumors, incorporating single-nuclei transcriptomic and chromatin accessibility sequencing, along with spatial profiling. We recovered tumor microenvironmental features previously described to associate with therapy response. We subsequently identified five malignant cell programs, including undifferentiated, intermediate, differentiated, epithelial-to-mesenchymal transition, and cycling programs, which were associated with differential epigenetic plasticity and clinical outcomes, and for which we inferred candidate transcription factor regulons. Furthermore, we revealed diverse spatial localizations of malignant cells expressing their associated transcriptional programs and predicted their significant interactions with microenvironmental cell types. We validated our findings in three external single-cell RNA-seq and three bulk RNA-seq studies. Altogether, our findings advance the understanding of EAC heterogeneity, disease progression, and therapeutic response.

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Josephine Yates, Camille Mathey-Andrews, Jihye Park, Amanda Garza, Andreanne Gagne, Samantha Hoffman, Kevin Bi, Breanna Titchen, Connor Hennessey, Joshua Remland, Matthew Carnes, Erin Shannon, Sabrina Camp, Siddhi Balamurali, Shweta Kiran Cavale, Zhixin Li, Akhouri Kishore Raghawan, Agnieszka Kraft, Genevieve Boland, Andrew J. Aguirre, Nilay S. Sethi, Valentina Boeva, Eliezer M. Van Allen. Cell states and neighborhoods in distinct clinical stages of primary and metastatic esophageal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Artificial Intelligence and Machine Learning; 2025 Jul 10-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(13_Suppl):Abstract nr A046.