Chromosomal instability shapes the tumor microenvironment of esophageal adenocarcinoma via a cGAS–chemokine–myeloid axis

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 <i>CXCL8</i> 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, <i>CXCL8</i> expression, and myeloid cell-mediated immunosuppression. In patients with EAC, CIN<sup>high</sup>, 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.

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Publication Details

Journal
Science Advances
Published
2026-03-11
DOI
https://doi.org/10.1126/sciadv.aeb1611
Primary Topic
interferon and immune responses
Type
article
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article

Chromosomal instability shapes the tumor microenvironment of esophageal adenocarcinoma via a cGAS–chemokine–myeloid axis

Nora Lawson, Erkin Erdal, Nicola Waddell, Ester M. Hammond et al.
Science Advances
interferon and immune responses
article

Chromosomal instability shapes the tumor microenvironment of esophageal adenocarcinoma via a cGAS–chemokine–myeloid axis

Nora Lawson, Erkin Erdal, Nicola Waddell, Ester M. Hammond, Bruno Beernaert, Shannique Clarke, Kadir C. Akdemir, Andréa E. Tijhuis, Stephen Ash, A. Carter, Alistair Easton, Simon Lord, Floris Foijer, Tong Liu, Molly Browne, DA Mann, T. Crosby, Zack D Brodtman, Frederik Stihler, Leticia Campo, Jack Leslie, Benjamin Izar, Eileen E. Parkes, Rabial Q. Raja, Ignacio Melero, Winston M. Zhu, Carlos E. de Andrea, Somnath Tagore, Rose L. Jady-Clark, Parin Shah, Juliet E. Martin, Erik Ramon-Gil
article en

Abstract

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 <i>CXCL8</i> 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, <i>CXCL8</i> expression, and myeloid cell-mediated immunosuppression. In patients with EAC, CIN<sup>high</sup>, 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.

Science AdvancesVol. 12(11)
The University of Texas MD Anderson Cancer Center (US), University of Groningen (NL), QIMR Berghofer Medical Research Institute (AU), Columbia University Irving Medical Center (US), University of Oxford (GB), Ludwig Cancer Research (GB), Clinica Universidad de Navarra (ES), Velindre Cancer Centre (GB), Centro de Investigación Biomédica en Red de Cáncer (ES), Newcastle University (GB)
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