TY - JOUR
T1 - Club cells employ regeneration mechanisms during lung tumorigenesis
AU - Chen, Yuanyuan
AU - Toth, Reka
AU - Chocarro, Sara
AU - Weichenhan, Dieter
AU - Hey, Joschka
AU - Lutsik, Pavlo
AU - Sawall, Stefan
AU - Stathopoulos, Georgios T.
AU - Plass, Christoph
AU - Sotillo, Rocio
N1 - Funding Information:
We are grateful to Severio Bellusci and Harold Chapman for providing Sftpc-CreER mice and to Claudia Scholl and Brigit Hogan for Scgb1a1-CreER and Foxj1-CreER mice. We thank Simone Kraut, Marion Bähr, the DKFZ Core Facilities of Light Microscopy, Flow Cytometry, Small Animal Imaging Center and Genomics and Proteomics for the excellent technical assistance; and the Central Animal Laboratory for animal husbandry. We appreciate the help of Jan-Philipp Mallm and the DKFZ Single-Cell Sequencing Open Lab in designing and conducting the scRNA-seq experiments. We wish to thank Alberto Diaz, Alicia Alonso, Maria Ramos and Kalman Somogyi for their suggestions on the manuscript. Schemes have been generated with BioRender.com. This work was supported by the Deutsches Zentrum für Lungenforschung (DZL, German Center for Lung Research # 82DZL004A4) to R.S. and C.P.; Y.C. and D.W. were supported by the Helmholtz Foundation. G.T.S. was supported by the Graduate College (Graduiertenkolleg, GRK) #2338 of the German Research Society (Deutsche Forschungsgemeinschaft, DFG), the target validation project for pharmaceutical development ALTERNATIVE of the German Ministry for Education and Research (Bundesministerium für Bildung und Forschung, BMBF) and a Translational Research Grant by the German Centre for Lung Research (DZL).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/8/5
Y1 - 2022/8/5
N2 - The high plasticity of lung epithelial cells, has for many years, confounded the correct identification of the cell-of-origin of lung adenocarcinoma (LUAD), one of the deadliest malignancies worldwide. Here, we employ lineage-tracing mouse models to investigate the cell of origin of Eml4-Alk LUAD, and show that Club and Alveolar type 2 (AT2) cells give rise to tumours. We focus on Club cell originated tumours and find that Club cells experience an epigenetic switch by which they lose their lineage fidelity and gain an AT2-like phenotype after oncogenic transformation. Single-cell transcriptomic analyses identified two trajectories of Club cell evolution which are similar to the ones used during lung regeneration, suggesting that lung epithelial cells leverage on their plasticity and intrinsic regeneration mechanisms to give rise to a tumour. Together, this study highlights the role of Club cells in LUAD initiation, identifies the mechanism of Club cell lineage infidelity, confirms the presence of these features in human tumours, and unveils key mechanisms conferring LUAD heterogeneity.
AB - The high plasticity of lung epithelial cells, has for many years, confounded the correct identification of the cell-of-origin of lung adenocarcinoma (LUAD), one of the deadliest malignancies worldwide. Here, we employ lineage-tracing mouse models to investigate the cell of origin of Eml4-Alk LUAD, and show that Club and Alveolar type 2 (AT2) cells give rise to tumours. We focus on Club cell originated tumours and find that Club cells experience an epigenetic switch by which they lose their lineage fidelity and gain an AT2-like phenotype after oncogenic transformation. Single-cell transcriptomic analyses identified two trajectories of Club cell evolution which are similar to the ones used during lung regeneration, suggesting that lung epithelial cells leverage on their plasticity and intrinsic regeneration mechanisms to give rise to a tumour. Together, this study highlights the role of Club cells in LUAD initiation, identifies the mechanism of Club cell lineage infidelity, confirms the presence of these features in human tumours, and unveils key mechanisms conferring LUAD heterogeneity.
KW - Adenocarcinoma of Lung/genetics
KW - Animals
KW - Cell Differentiation/genetics
KW - Cell Transformation, Neoplastic/pathology
KW - Epithelial Cells/pathology
KW - Humans
KW - Lung/pathology
KW - Lung Neoplasms/genetics
KW - Mice
UR - http://www.scopus.com/inward/record.url?scp=85135574792&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/35931677
U2 - 10.1038/s41467-022-32052-2
DO - 10.1038/s41467-022-32052-2
M3 - Article
C2 - 35931677
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4557
ER -