An entosis-informed prognostic index for survival stratification and molecular characterization in lung adenocarcinoma.
6 affiliations
- 1Department of Traditional Chinese Medicine Preventive Healthcare, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- 2Department of Thoracic Surgery, Tongren Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- 3Institute of Respiratory Diseases, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- 4The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, China.
- 5Department of Internal Medicine of Oncology and Hematology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China.
- 6Department of Respiratory Endoscopy, Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract
Background
Entosis is an actomyosin-dependent cell-in-cell process that may culminate in lysosome-mediated entotic cell death and is implicated in tumor evolution. Its clinical relevance in lung adenocarcinoma (LUAD) remains unclear.Methods
To construct an Entosis-related Prognostic Prediction Index (EPPI), this study integrated TCGA-LUAD transcriptomic, clinical, and somatic mutation data. Three independent GEO cohorts provided external validation. The initial candidate gene set covered components driving cell-in-cell formation and the intracellular degradation of internalized cells. For subgroup comparison, the analytical approach incorporated survival analysis, functional enrichment, tumor microenvironment profiling, mutation analysis, immunotherapy assessment, and drug-sensitivity prediction. Tissue and cellular distributions of the EPPI genes were mapped using spatial transcriptomics and single-cell RNA sequencing. Molecular docking assessed predicted drug-target interactions. Finally, in vitro RAC1 knockdown experiments evaluated the cellular function of a representative EPPI gene.Results
Comprising RND3, RAC1, KRAS, CTNNA1, AURKA, and ACTB, the final EPPI consistently stratified overall survival across all cohorts and showed moderate prognostic discrimination. The high-EPPI group had greater tumor purity and mutational burden, with enhanced cell-cycle, DNA-repair, epithelial-mesenchymal transition, and NF-κB programs, whereas the low-EPPI group showed greater immune and stromal infiltration. TIDE and immunophenoscores also differed between subgroups. Drug-response models predicted greater sensitivity to cisplatin and paclitaxel in the high-EPPI group and to several targeted agents in the low-EPPI group. Molecular docking predicted RAC1-EHT-1864 and AURKA-alisertib interactions. Spatial and single-cell analyses showed heterogeneous EPPI-gene expression, with ACTB and RAC1 broadly distributed and AURKA restricted to selected populations. RAC1 depletion suppressed LUAD-cell proliferation, DNA synthesis, migration, and invasion.Conclusion
The EPPI is an entosis-informed prognostic index for survival stratification in LUAD. Based on this index, patients can be separated into subgroups with distinct proliferative features, genomic alterations, tissue compositions, and predicted drug sensitivities. These findings associate entosis-related molecular features with distinct cellular and clinical characteristics of LUAD.
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BibTeX
@article{liu2026entosisinformed,
title = {{An entosis-informed prognostic index for survival stratification and molecular characterization in lung adenocarcinoma.}},
author = {Yinqin Liu and Wen Zhao and Shuyi Mu and Silun Liang and Yanping Wen and Shaobin Li and Chengyan Zhan and Yanqi Cheng and Ling Tang and Yuqin Wu and Ziyou Lin and Hong Fang and Yubin Ding},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1943127},
url = {https://europepmc.org/article/MED/42898290},
note = {CC BY},
}
RIS
TY - JOUR
TI - An entosis-informed prognostic index for survival stratification and molecular characterization in lung adenocarcinoma.
AU - Yinqin Liu
AU - Wen Zhao
AU - Shuyi Mu
AU - Silun Liang
AU - Yanping Wen
AU - Shaobin Li
AU - Chengyan Zhan
AU - Yanqi Cheng
AU - Ling Tang
AU - Yuqin Wu
AU - Ziyou Lin
AU - Hong Fang
AU - Yubin Ding
PY - 2026
DA - 2026/10/05
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1943127
UR - https://europepmc.org/article/MED/42898290
AB - Background Entosis is an actomyosin-dependent cell-in-cell process that may culminate in lysosome-mediated entotic cell death and is implicated in tumor evolution. Its clinical relevance in lung adenocarcinoma (LUAD) remains unclear.Methods To construct an Entosis-related Prognostic Prediction Index (EPPI), this study integrated TCGA-LUAD transcriptomic, clinical, and somatic mutation data. Three independent GEO cohorts provided external validation. The initial candidate gene set covered components driving cell-in-cell formation and the intracellular degradation of internalized cells. For subgroup comparison, the analytical approach incorporated survival analysis, functional enrichment, tumor microenvironment profiling, mutation analysis, immunotherapy assessment, and drug-sensitivity prediction. Tissue and cellular distributions of the EPPI genes were mapped using spatial transcriptomics and single-cell RNA sequencing. Molecular docking assessed predicted drug-target interactions. Finally, in vitro RAC1 knockdown experiments evaluated the cellular function of a representative EPPI gene.Results Comprising RND3, RAC1, KRAS, CTNNA1, AURKA, and ACTB, the final EPPI consistently stratified overall survival across all cohorts and showed moderate prognostic discrimination. The high-EPPI group had greater tumor purity and mutational burden, with enhanced cell-cycle, DNA-repair, epithelial-mesenchymal transition, and NF-κB programs, whereas the low-EPPI group showed greater immune and stromal infiltration. TIDE and immunophenoscores also differed between subgroups. Drug-response models predicted greater sensitivity to cisplatin and paclitaxel in the high-EPPI group and to several targeted agents in the low-EPPI group. Molecular docking predicted RAC1-EHT-1864 and AURKA-alisertib interactions. Spatial and single-cell analyses showed heterogeneous EPPI-gene expression, with ACTB and RAC1 broadly distributed and AURKA restricted to selected populations. RAC1 depletion suppressed LUAD-cell proliferation, DNA synthesis, migration, and invasion.Conclusion The EPPI is an entosis-informed prognostic index for survival stratification in LUAD. Based on this index, patients can be separated into subgroups with distinct proliferative features, genomic alterations, tissue compositions, and predicted drug sensitivities. These findings associate entosis-related molecular features with distinct cellular and clinical characteristics of LUAD.
SN - 2296-634X
ER -