NNK関連の腫瘍リモデリングと膵臓がんの予後層別化を解読する統合マルチオミクスおよびラジオゲノムプロファイリング
Zongyu Xie1, Yuan Fang1, Jingcheng Huang1
1Department of Radiology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
Objective:
To elucidate how the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) relates to pancreatic cancer (PC) progression and to develop a CT-based radiomics model that non-invasively decodes NNK-related molecular alterations.
Methods:
NNK-related genes were identified by integrating toxicogenomic mining across multiple databases with multi-cohort transcriptomic analyses. Differential expression analysis, weighted gene coexpression network analysis (WGCNA), a multi-algorithm machine-learning framework, and Cox proportional hazards modeling were applied to screen key regulators and prognosis-related factors. Single-cell RNA sequencing was performed to characterize cellular heterogeneity and tumor-stroma communication associated with ITGA3. Radiomic features were extracted from CT scans, and a radiomics signature was constructed. Prognostic value was evaluated in the cancer imaging archive (TCIA), and an independent surgical cohort.
Results:
A total of 268 NNK-associated PC genes were identified, enriched in extracellular matrix (ECM) remodeling, focal adhesion, PI3K-AKT signaling, and DNA-damage response pathways. Machine-learning prioritization yielded 15 key candidates, among which ITGA3 remained an independent prognostic factor (P < 0.05). Single-cell analysis showed enrichment of basal/epithelial-mesenchymal transition (EMT)-high epithelial subsets and intensified epithelial-cancer-associated fibroblast-macrophage communication in ITGA3-high tumors. The NNK-related ITGA3-guided radiomics model predicted ITGA3 expression (AUC = 0.893 and 0.839) and achieved significant postoperative survival stratification.
Conclusion:
NNK is associated with a malignant transcriptional program characterized by epithelial remodeling, stromal interaction, and immune suppression. These molecular features can be captured non-invasively through CT-based radiomics. The NNK-related ITGA3-associated radiomics (NIR) score provides a practical tool for preoperative risk stratification in PC and offers a bridge linking environmental carcinogen exposure with tumor imaging phenotypes.
