
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.17.608386
preprint
2
Article
Cell states and neighborhoods in distinct clinical stages of primary and metastatic esophageal adenocarcinoma
Yates Josephine http://orcid.org/0000-0001-8346-4502

Mathey-Andrews Camille
Park Jihye http://orcid.org/0000-0002-4451-2046

Garza Amanda
Gagné Andréanne http://orcid.org/0000-0002-3833-4159

Hoffman Samantha http://orcid.org/0000-0002-6752-172X

Bi Kevin
Titchen Breanna
Hennessey Connor http://orcid.org/0000-0002-5579-1220

Remland Joshua http://orcid.org/0009-0004-5655-0762

Shannon Erin
Camp Sabrina
Balamurali Siddhi
Cavale Shweta Kiran
Li Zhixin http://orcid.org/0000-0001-9962-3942

Raghawan Akhouri Kishore
Kraft Agnieszka http://orcid.org/0000-0001-7672-2032

Boland Genevieve
Aguirre Andrew J. http://orcid.org/0000-0002-0701-6203

Sethi Nilay S. http://orcid.org/0000-0002-3748-7559

Boeva Valentina http://orcid.org/0000-0002-4382-7185

Van Allen Eliezer http://orcid.org/0000-0002-0201-4444

20 8 2024
2024.08.17.608386https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.17.608386
nihpp-2024.08.17.608386.pdf
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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pmc
