Dissecting the Radioresponse Heterogeneity of Lung Adenocarcinoma Cells From the Perspective of Transcriptional and Regulatory Landscape.
- 1Academy of Military Medical Sciences Beijing China.
- 2Center for Statistical Science Center for Bioinformatics School of Life Sciences Peking University Beijing China.
Abstract
Radioresistance severely compromises radiotherapy efficacy for lung adenocarcinoma (LUAD), yet the intrinsic heterogeneity of cellular radioresponses among isogenic tumor cells remains poorly characterized. Here, we integrated single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin with high-throughput sequencing (scATAC-seq) to dissect the transcriptional and regulatory landscape underlying heterogeneous radioresponses in single-cell-derived LUAD cells following 6 Gy γ-ray irradiation. We found that isogenic LUAD cells harbored intrinsic molecular determinants for divergent radiosensitivity and displayed heterogeneous radioresponsiveness upon irradiation. A radiation-associated transcriptional cell state, coupled with DNA damage repair, apoptosis, and cell cycle regulation, emerged at 6 h post-irradiation. Inhibition of lysine demethylase 4B (KDM4B) enhanced LUAD radiosensitivity by intensifying DNA damage, whereas reduced expression of cyclin B1 (CCNB1) and DNA topoisomerase IIα (TOP2A) potentially contributed to radiation-triggered G2/M arrest. Notably, the radiation-associated regulatory cell state emerged earlier than radiation-induced transcriptional cell state. RNA polymerase II subunit A (POLR2A) functioned as a core regulator in high-responsive LUAD cells. Based on these findings, we proposed a hypothesis for the radiosensitization of LUAD cells. Collectively, this study provides multilayer mechanistic insights into LUAD radioresponse heterogeneity and yields actionable molecular candidates for developing improved radiosensitization strategies to advance precise radiotherapy for LUAD.
Related
- Spatially dissecting drivers of inter- and intra-tumoral heterogeneity in Kenyan breast cancer.
- Arrest-associated transcriptional programmes outweigh apoptosis-associated programmes in treatment-naive pancreatic ductal adenocarcinoma
- Integrative Bioinformatics, Experimental Validation, and Interpretable Machine Learning Reveal Oxyresveratrol‐Mediated Protection Against Cadmium‐Induced Lung Adenocarcinoma‐Related Transcriptional Dysregulation
- Gene context shapes spatial organization and transcriptional heterogeneity of extrachromosomal DNA in cancer cells
- CLDN18.2 in pancreatic ductal adenocarcinoma: Biomarker assessment, spatial heterogeneity and therapeutic modality selection
BibTeX
@article{tao2026dissecting,
title = {{Dissecting the Radioresponse Heterogeneity of Lung Adenocarcinoma Cells From the Perspective of Transcriptional and Regulatory Landscape.}},
author = {Huan Tao and Yaru Li and Leixin Ge and Lu Chen and Yang Zheng and Feiyue Ma and Changhui Ge and Hanjiang Fu and Yu Sun and Longteng Wang and Junting Wang and Xuemei Bai and Hao Li and Xiaochen Bo and Hebing Chen and Xiaofei Zheng},
journal = {MedComm},
year = {2026},
month = oct,
doi = {10.1002/mco2.71071},
url = {https://europepmc.org/article/MED/42910072},
note = {CC BY},
}
RIS
TY - JOUR
TI - Dissecting the Radioresponse Heterogeneity of Lung Adenocarcinoma Cells From the Perspective of Transcriptional and Regulatory Landscape.
AU - Huan Tao
AU - Yaru Li
AU - Leixin Ge
AU - Lu Chen
AU - Yang Zheng
AU - Feiyue Ma
AU - Changhui Ge
AU - Hanjiang Fu
AU - Yu Sun
AU - Longteng Wang
AU - Junting Wang
AU - Xuemei Bai
AU - Hao Li
AU - Xiaochen Bo
AU - Hebing Chen
AU - Xiaofei Zheng
PY - 2026
DA - 2026/10/21
JO - MedComm
DO - 10.1002/mco2.71071
UR - https://europepmc.org/article/MED/42910072
AB - Radioresistance severely compromises radiotherapy efficacy for lung adenocarcinoma (LUAD), yet the intrinsic heterogeneity of cellular radioresponses among isogenic tumor cells remains poorly characterized. Here, we integrated single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin with high-throughput sequencing (scATAC-seq) to dissect the transcriptional and regulatory landscape underlying heterogeneous radioresponses in single-cell-derived LUAD cells following 6 Gy γ-ray irradiation. We found that isogenic LUAD cells harbored intrinsic molecular determinants for divergent radiosensitivity and displayed heterogeneous radioresponsiveness upon irradiation. A radiation-associated transcriptional cell state, coupled with DNA damage repair, apoptosis, and cell cycle regulation, emerged at 6 h post-irradiation. Inhibition of lysine demethylase 4B (KDM4B) enhanced LUAD radiosensitivity by intensifying DNA damage, whereas reduced expression of cyclin B1 (CCNB1) and DNA topoisomerase IIα (TOP2A) potentially contributed to radiation-triggered G2/M arrest. Notably, the radiation-associated regulatory cell state emerged earlier than radiation-induced transcriptional cell state. RNA polymerase II subunit A (POLR2A) functioned as a core regulator in high-responsive LUAD cells. Based on these findings, we proposed a hypothesis for the radiosensitization of LUAD cells. Collectively, this study provides multilayer mechanistic insights into LUAD radioresponse heterogeneity and yields actionable molecular candidates for developing improved radiosensitization strategies to advance precise radiotherapy for LUAD.
SN - 2688-2663
ER -