From chronic airway injury to lung cancer: epithelial memory, field cancerization, and premalignant evolution
- 1Department of Thoracic Surgery, Ninghai County First Hospital
- 2Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine
Abstract
Chronic airway injury induced by tobacco smoke, environmental pollutants, and persistent inflammatory lung diseases provides a biological foundation for lung carcinogenesis, yet the cellular and molecular trajectory from repeated epithelial damage to invasive malignancy has only recently come into focus. Here we synthesize three interconnected concepts that together define this trajectory: epithelial memory, the capacity of airway basal and secretory cells to retain epigenetic and transcriptional scars long after the initial insult has ceased; field cancerization, whereby histologically normal-appearing airway epithelium harbours widespread clonal alterations that expand the pool of at-risk cells; and premalignant evolution, the Darwinian selection and diversification of clones as genetic, epigenetic, immune, and metabolic pressures reshape the altered field. We review evidence from single-cell genomics, spatial transcriptomics, and longitudinal human cohort studies that reveals how smoking-associated DNA methylation marks, persistent chromatin accessibility changes, and rewired transcriptional programmes establish an epigenetically primed epithelial landscape. Within this landscape, somatic driver mutations in TP53, KRAS, NOTCH1, and chromatin remodelling genes confer competitive fitness advantages, enabling clonal expansion across large territories of the bronchial tree. We propose an integrative model in which epigenetic priming, somatic mutation, clonal competition, immune surveillance, and metabolic constraints interact over years to decades, without assuming a universal fixed sequence across all lung cancer subtypes. This framework identifies actionable interception windows — from epigenetic reversal of injury memory to targeted elimination of premalignant clones — and highlights the need for longitudinal single-cell atlases and lineage-resolved models to resolve the causal ordering of molecular events. We conclude that lung cancer is best understood not as an abrupt cellular transformation but as the end point of a protracted, spatially distributed evolutionary process whose earliest stages may be reversible.
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BibTeX
@article{wang2026from,
title = {{From chronic airway injury to lung cancer: epithelial memory, field cancerization, and premalignant evolution}},
author = {Wenhui Wang and Xueyang Ji and Zhibo Chang},
journal = {Frontiers in Oncology},
year = {2026},
month = nov,
doi = {10.3389/fonc.2026.1946364},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1946364/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - From chronic airway injury to lung cancer: epithelial memory, field cancerization, and premalignant evolution
AU - Wenhui Wang
AU - Xueyang Ji
AU - Zhibo Chang
PY - 2026
DA - 2026/11/04
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1946364
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1946364/full
AB - Chronic airway injury induced by tobacco smoke, environmental pollutants, and persistent inflammatory lung diseases provides a biological foundation for lung carcinogenesis, yet the cellular and molecular trajectory from repeated epithelial damage to invasive malignancy has only recently come into focus. Here we synthesize three interconnected concepts that together define this trajectory: epithelial memory, the capacity of airway basal and secretory cells to retain epigenetic and transcriptional scars long after the initial insult has ceased; field cancerization, whereby histologically normal-appearing airway epithelium harbours widespread clonal alterations that expand the pool of at-risk cells; and premalignant evolution, the Darwinian selection and diversification of clones as genetic, epigenetic, immune, and metabolic pressures reshape the altered field. We review evidence from single-cell genomics, spatial transcriptomics, and longitudinal human cohort studies that reveals how smoking-associated DNA methylation marks, persistent chromatin accessibility changes, and rewired transcriptional programmes establish an epigenetically primed epithelial landscape. Within this landscape, somatic driver mutations in TP53, KRAS, NOTCH1, and chromatin remodelling genes confer competitive fitness advantages, enabling clonal expansion across large territories of the bronchial tree. We propose an integrative model in which epigenetic priming, somatic mutation, clonal competition, immune surveillance, and metabolic constraints interact over years to decades, without assuming a universal fixed sequence across all lung cancer subtypes. This framework identifies actionable interception windows — from epigenetic reversal of injury memory to targeted elimination of premalignant clones — and highlights the need for longitudinal single-cell atlases and lineage-resolved models to resolve the causal ordering of molecular events. We conclude that lung cancer is best understood not as an abrupt cellular transformation but as the end point of a protracted, spatially distributed evolutionary process whose earliest stages may be reversible.
SN - 2234-943X
ER -