TY - JOUR T1 - A role for club cells in smoking-associated lung adenocarcinoma JF - European Respiratory Review JO - EUROPEAN RESPIRATORY REVIEW DO - 10.1183/16000617.0122-2021 VL - 30 IS - 162 SP - 210122 AU - Sabine J. Behrend AU - Georgia A. Giotopoulou AU - Magda Spella AU - Georgios T. Stathopoulos Y1 - 2021/12/31 UR - http://err.ersjournals.com/content/30/162/210122.abstract N2 - The cellular origin of lung adenocarcinoma remains a focus of intense research efforts. The marked cellular heterogeneity and plasticity of the lungs, as well as the vast variety of molecular subtypes of lung adenocarcinomas perplex the field and account for the extensive variability of experimental results. While most experts would agree on the cellular origins of other types of thoracic tumours, great controversy exists on the tumour-initiating cells of lung adenocarcinoma, since this histologic subtype of lung cancer arises in the distal pulmonary regions where airways and alveoli converge, occurs in smokers as well as nonsmokers, is likely caused by various environmental agents, and is marked by vast molecular and pathologic heterogeneity. Alveolar type II, club, and their variant cells have all been implicated in lung adenocarcinoma progeny and the lineage hierarchies in the distal lung remain disputed. Here we review the relevant literature in this rapidly expanding field, including results from mouse models and human studies. In addition, we present a case for club cells as cells of origin of lung adenocarcinomas that arise in smokers.Multiple lung epithelial cells are targets of carcinogenic hits. Club cells are such cells that can metabolically activate tobacco pre-carcinogens, being thus positioned as cells of origin of lung adenocarcinomas in smokers. https://bit.ly/3iOshcy ER -