Multi‐Omics Integration Identifies a CDH3‐Associated Malignant Epithelial State and Immunosuppressive Niche to Predict Prognosis in Thymic Epithelial Tumors
- 1Department of Thoracic Surgery School of Medicine Shanghai Pulmonary Hospital Tongji University Shanghai China
- 2Department of Thoracic Surgery Ningbo Second Hospital Ningbo China
Abstract
Thymic epithelial tumors (TETs) are rare and heterogeneous malignancies whose aggressive epithelial states and microenvironmental organization remain poorly defined. Here, we integrated single‐cell RNA sequencing, spatial transcriptomics, multiplex immunofluorescence, bulk transcriptomics, functional assays, xenograft validation, and computational pathology to characterize malignant epithelial heterogeneity in TETs. We identified a CDH3‐associated malignant epithelial state located at the origin of malignant‐state trajectories and enriched for stem‐like and EMT‐related features. Spatial transcriptomics and multiplex immunofluorescence showed that CDH3+ tumor cells preferentially localized within an M2 macrophage‐rich immunosuppressive niche, while cell–cell communication analyses nominated CCN2–LRP1 as a candidate epithelial–myeloid crosstalk axis. A 68‐gene CDH3‐associated signature stratified TCGA‐THYM into biologically distinct subgroups with differences in survival, histology, genomic instability, and immune contexture. Patient‐derived thymic carcinoma organoids showed elevated CDH3 expression, and CDH3 silencing suppressed thymic carcinoma cell proliferation, migration, invasion, EMT/PI3K–Akt‐related signaling, and macrophage‐associated crosstalk. Candidate inhibitors showed antitumor activity in xenograft models. We also established a deep learning pathology model that captured CDH3‐associated morphology from routine H&E slides and predicted patient outcome. Together, these findings define CDH3 as a biomarker and therapeutic target linking malignant epithelial plasticity to immunosuppressive niche formation and adverse clinical behavior in TETs.
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BibTeX
@article{feng2026multiomics,
title = {{Multi‐Omics Integration Identifies a CDH3‐Associated Malignant Epithelial State and Immunosuppressive Niche to Predict Prognosis in Thymic Epithelial Tumors}},
author = {Yuntao Feng and Jingyu Chen and Lang Xia and Tao Wang and Yuzhou Wang and Lei Zhang and Guofang Zhao and Long Xu and Juemin Yu and Yunlang She and Junqi Wu and Yue Zhao and Chang Chen and Deping Zhao},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77153},
url = {https://doi.org/10.1002/advs.77153},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Multi‐Omics Integration Identifies a CDH3‐Associated Malignant Epithelial State and Immunosuppressive Niche to Predict Prognosis in Thymic Epithelial Tumors
AU - Yuntao Feng
AU - Jingyu Chen
AU - Lang Xia
AU - Tao Wang
AU - Yuzhou Wang
AU - Lei Zhang
AU - Guofang Zhao
AU - Long Xu
AU - Juemin Yu
AU - Yunlang She
AU - Junqi Wu
AU - Yue Zhao
AU - Chang Chen
AU - Deping Zhao
PY - 2026
DA - 2026/08/15
JO - Advanced Science
DO - 10.1002/advs.77153
UR - https://doi.org/10.1002/advs.77153
AB - Thymic epithelial tumors (TETs) are rare and heterogeneous malignancies whose aggressive epithelial states and microenvironmental organization remain poorly defined. Here, we integrated single‐cell RNA sequencing, spatial transcriptomics, multiplex immunofluorescence, bulk transcriptomics, functional assays, xenograft validation, and computational pathology to characterize malignant epithelial heterogeneity in TETs. We identified a CDH3‐associated malignant epithelial state located at the origin of malignant‐state trajectories and enriched for stem‐like and EMT‐related features. Spatial transcriptomics and multiplex immunofluorescence showed that CDH3+ tumor cells preferentially localized within an M2 macrophage‐rich immunosuppressive niche, while cell–cell communication analyses nominated CCN2–LRP1 as a candidate epithelial–myeloid crosstalk axis. A 68‐gene CDH3‐associated signature stratified TCGA‐THYM into biologically distinct subgroups with differences in survival, histology, genomic instability, and immune contexture. Patient‐derived thymic carcinoma organoids showed elevated CDH3 expression, and CDH3 silencing suppressed thymic carcinoma cell proliferation, migration, invasion, EMT/PI3K–Akt‐related signaling, and macrophage‐associated crosstalk. Candidate inhibitors showed antitumor activity in xenograft models. We also established a deep learning pathology model that captured CDH3‐associated morphology from routine H&E slides and predicted patient outcome. Together, these findings define CDH3 as a biomarker and therapeutic target linking malignant epithelial plasticity to immunosuppressive niche formation and adverse clinical behavior in TETs.
SN - 2198-3844
ER -