PD05.09. Spatial Multi-Omics Reveals Co-Evolution of Cancer Cells and Tumor Microenvironment During Esophageal Cancer Progression

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ID: 326105
2026
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Ranked #429 of 453 articles by views in diseases of the esophagus : official journal of the international society for diseases of the esophagus

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Abstract
Abstract Topic Esophageal Cancer: Molecular Biology/Pathology Background Spatial transcriptomic profiling was performed using the Xenium Prime 5K platform on treatment-naïve ESCC primary tumors (n=10) spanning mucosal to deep submucosal invasion, matched metastatic lymph nodes (n=11), and normal tissues (n=3). After QC filtering, 8,284,705 cells were classified into nine major cell types. Cancer cells were subclustered per sample using consensus non-negative matrix factorization (cNMF) to delineate spatially distinct subpopulations. To link transcriptomic phenotypes with clonal architecture, LCM-based whole genome sequencing was performed on 20 regions from 3 patients, enabling phylogenetic reconstruction across primary tumors and matched metastatic lymph nodes. Methods Cancer cell analysis revealed two independent axes of variation. The first axis stratified tumors into NRF2-high and NRF2-low subtypes regardless of invasion depth. NRF2-high tumors showed reduced immune infiltration, consistent with NRF2 pathway enrichment in non-responders from an independent neoadjuvant immunochemotherapy cohort. The second axis reflected invasion depth-dependent progression, where deeper tumors acquired EMT features alongside the emergence of COL10A1+COL11A1+ myCAFs that drove desmoplastic reactions at the tumor-stromal interface. Metastatic lymph nodes showed two distinct stromal patterns: those with desmoplastic reactions and those without. Phylogenetic reconstruction revealed that metastatic lymph nodes lacking desmoplastic reactions branched early from primary tumor clones, consistent with dissemination prior to stromal remodeling. Results Integrating spatial transcriptomics with LCM-based WGS, we identified two axes underlying ESCC heterogeneity. NRF2-driven immune exclusion is relevant to immunotherapy resistance, while EMT-driven co-evolution with COL10A1+COL11A1+ myCAFs induces desmoplastic reactions. Phylogenetic analysis confirms that metastatic lymph nodes without desmoplastic reactions arose through early dissemination. These findings provide new insights into immune evasion mechanisms and metastatic timing in ESCC. Conclusion Integrating spatial transcriptomics with LCM-based WGS, we identified two axes underlying ESCC heterogeneity. NRF2-driven immune exclusion is relevant to immunotherapy resistance, while EMT-driven co-evolution with COL10A1+COL11A1+ myCAFs induces desmoplastic reactions. Phylogenetic analysis confirms that metastatic lymph nodes without desmoplastic reactions arose through early dissemination. These findings provide new insights into immune evasion mechanisms and metastatic timing in ESCC.
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Authors Jangwo N OH, Sung Yong Park, Jong-Eun Park
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Journal diseases of the esophagus : official journal of the international society for diseases of the esophagus
Year 2026
DOI
10.1093/dote/doag077.112
URL
https://academic.oup.com/dote/article-pdf/39/Supplement_1/doag077.112/70760427/doag077.112.pdf
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