|Song, Hai -|
|Yao, Erica -|
|Lin, Chuwen -|
|Gacayan, Rhodora -|
|Chen, Miao-Hsueh -|
|Chuang, Pao-Tien -|
Submitted to: Proceedings of the National Academy of Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: September 14, 2012
Publication Date: October 23, 2012
Citation: Song, H., Yao, E., Lin, C., Gacayan, R., Chen, M., Chuang, P. 2012. Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis. Proceedings of the National Academy of Sciences. 109(43):17531-17536. Interpretive Summary: The lung is the major organ that delivers oxygen to and removes carbon dioxide from our body. The lung contains more than 40 different types of cells, including lung neuroendocrine cells. Very little is known regarding where lung neuroendocrine cells originate during development and how these cells function in adults. Recent studies suggested that lung neuroendocrine cells might be the cells from which small-cell lung cancer arises in humans. In order to understand how lung neuroendocrine cells develop and how these cells might contribute to small-cell lung cancer, we generated genetically modified CGRPCreER mice. By mating these mice with various reporter mouse lines, we were able to track the location of lung neuroendocrine cells throughout the course of development. We found that lung neuroendocrine cells develop from the progenitor cells in the lung epithelium. In addition, we also found that lung neuroendocrine cells can serve as progenitor cells that produce new lung cells after lung injury. Finally, by mating CGRPCreER mice with mice carrying mutations in genes involved in tumor development, we verified that lung neuroendocrine cells could develop into small-cell lung cancer. Taken together, our studies provide new insights into the roles of lung neuroendocrine cells in development, lung injury, and the formation of small-cell lung cancer.
Technical Abstract: Pulmonary neuroendocrine cells (PNECs) are proposed to be the first specialized cell type to appear in the lung, but their ontogeny remains obscure. Although studies of PNECs have suggested their involvement in a number of lung functions, neither their in vivo significance nor the molecular mechanisms underlying them have been elucidated. Importantly, PNECs have long been speculated to constitute the cells of origin of human small-cell lung cancer (SCLC), and recent mouse models support this hypothesis. However, a genetic system that permits tracing the early events of PNEC transformation has not been available. To address these key issues, we developed a genetic tool in mice by introducing a fusion protein of Cre recombinase and estrogen receptor (CreER) into the "calcitonin gene-related peptide (CGRP)" locus that encodes a major peptide in PNECs. The "CGRP(CreER)" mouse line has enabled us to manipulate gene activity in PNECs. Lineage tracing using this tool revealed the plasticity of PNECs. PNECs can be colabeled with alveolar cells during lung development, and following lung injury, PNECs can contribute to Clara cells and ciliated cells. Contrary to the current model, we observed that elimination of PNECs has no apparent consequence on Clara cell recovery. We also created mouse models of SCLC in which "CGRP(CreER)" was used to ablate multiple tumor suppressors in PNECs that were simultaneously labeled for following their fate. Our findings suggest that SCLC can originate from differentiated PNECs. Together, these studies provide unique insight into PNEC lineage and function and establish the foundation of investigating how PNECs contribute to lung homeostasis, injury/repair, and tumorigenesis.