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Lookup NU author(s): Erik Ramon Gil, rabial raja, Professor Derek MannORCiD, Dr Jack LeslieORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Chromosomal instability (CIN), a pervasive feature of esophageal adenocarcinoma (EAC), drives tumor aggressiveness and metastasis. CIN stimulates the cGAS-STING pathway, typically linked to antitumor immunity. However, despite the high CIN burden in EAC, the cGAS-STING pathway remains largely intact. To address this paradox, we interrogated multiple esophageal cancer models, finding myeloid-attracting chemokines-with CXCL8 as a prominent hit-as conserved CIN-driven targets in EAC. Using multiplexed immunofluorescence microscopy, we quantified ongoing CIN in human EAC tumors by measuring cGAS-positive micronuclei, validated by whole-genome sequencing. Coupling in situ CIN detection with single-nucleus RNA sequencing and multiplex immunophenotyping of human EAC, we link CIN to tumor-intrinsic innate immune activation, CXCL8 expression, and myeloid cell-mediated immunosuppression. In patients with EAC, CINhigh, myeloid-dominated tumors correlate with poor outcomes and aberrant cGAS-STING signaling. These insights explain the counterintuitive maintenance of cGAS-STING and highlight the disruption of the CIN-cGAS-inflammation axis as a potential therapeutic strategy in EAC.
Author(s): Beernaert B, Jady-Clark RL, Shah P, Ramon-Gil E, Lawson NM, Brodtman ZD, Tagore S, Stihler F, Carter AS, Clarke S, Liu T, Zhu WM, Martin JE, Erdal E, Easton A, Campo L, Browne M, Ash S, Raja RQ, Waddell N, Crosby T, Lord SR, Mann DA, Melero I, de Andrea CE, Tijhuis AE, Foijer F, Hammond EM, Akdemir KC, Leslie J, Izar B, Parkes EE
Publication type: Article
Publication status: Published
Journal: Science Advances
Year: 2026
Volume: 12
Issue: 11
Print publication date: 13/03/2026
Online publication date: 11/03/2026
Acceptance date: 09/02/2026
Date deposited: 07/04/2026
ISSN (electronic): 2375-2548
Publisher: American Association for the Advancement of Science
URL: https://doi.org/10.1126/sciadv.aeb1611
DOI: 10.1126/sciadv.aeb1611
Data Access Statement: All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials. New materials generated in this study are available upon request from the corresponding author E.E.P. at eileen.parkes@oncology.ox.ac.uk. All transcriptomic data generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) database. RNA-seq data for the isogenic CP-A cell model and cGASKO EAC cells have been deposited under accession codes GSE316127 and GSE315942, respectively. snRNA-seq data have been deposited under accession code GSE316062. Raw scWGS data of CP-A cell lines have been submitted to the NCBI Sequence Read Archive (SRA) database under accession code PRJNA1399717. Raw WGS data for human EAC tumors are available at the European Genome-Phenome Archive (EGA) under accession code EGAS50000001561 through a data access agreement with the University of Oxford.
PubMed id: 41811963
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