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

食管腺癌 腺癌 医学 小学(天文学) 病理 肿瘤科 原发性肿瘤 内科学 转移 癌症 天文 物理
作者
Josephine Yates,Camille Mathey-Andrews,Jihye Park,Amanda Garza,Andréanne Gagné,Samantha E. Hoffman,Kevin Bi,Breanna Titchen,Connor J. Hennessey,Joshua Remland,Erin Shannon,Sabrina Y. Camp,Siddhi Balamurali,Shweta Kiran Cavale,Zhixin Li,Akhouri Kishore Raghawan,Agnieszka Kraft,Genevieve M. Boland,Andrew J. Aguirre,Nilay S. Sethi,Valentina Boeva,Eliezer M. Van Allen
标识
DOI:10.1101/2024.08.17.608386
摘要

Abstract 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 identified tumor microenvironmental features previously described to associate with therapy response. We 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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