Alveolar Type II Cells Possess the Capability of Initiating Lung Tumor Development

Abstract

Identifying cells of tumor origin is a fundamental question in tumor biology. Answers to this central question will not only advance our understanding of tumor initiation and progression but also have important therapeutic implications. In this study, we aimed to uncover the cells of origin of lung adenocarcinoma, a major subtype of non-small cell lung cancer. To this end, we developed new mouse models of lung adenocarcinoma that enabled selective manipulation of gene activity in surfactant associated protein C (SPC)-expressing cells, including alveolar type II cells and bronchioalveolar stem cells (BASCs) that reside at the bronchioalveolar duct junction (BADJ). Our findings showed that activation of oncogenic Kras alone or in combination with the removal of the tumor suppressor p53 in SPC+ cells resulted in development of alveolar tumors. Similarly, sustained EGF signaling in SPC+ cells led to alveolar tumors. By contrast, BASCs failed to proliferate or produce tumors under these conditions. Importantly, in a mouse strain in which Kras/p53 activity was selectively altered in type II cells but not BASCs, alveolar tumors developed while BADJs retained normal architecture. These results confirm and extend previous findings and support a model in which lung adenocarcinoma can initiate in alveolar type II cells. Our results establish the foundation for elucidating the molecular mechanisms by which lung cancer initiates and progresses in a specific lung cell type.

Transforming growth factor-beta signaling network regulates plasticity and lineage commitment of lung cancer cells

“…These data are consistent with previous reports showing that putative BASCs are not the only cell type that gives rise to KrasG12D-driven tumors. 14,17 More importantly, they demonstrate that our cultures contain cells with the potential to give rise to at least three different types of lung cancers, despite their apparent genetic and immunophenotypic similarity.…”

“…BASC cells are defined by the surface phenotype of EpCAM þ SCA1 þ CD34 þ and expression of both SpC (AT2 cell marker) and CC10 (Clara cell marker). 12,14,17 Approximately 5% of our LSL KrasG12D p53 KO cells were also positive in CD34 staining (Supplementary Figure 2). However, we found virtually no CC10 þ or SpC þ cells, implying that our cultures were not enriched in BASC-like cells.…”

“…The cell(s) of origin of NSCLC has not been formally identified, although AT2 cells and the putative BASCs have been proposed as initiating cell sources for lung ADC. 12,14,17 Here, we modeled the development of NSCLC using primary cells derived from crosses of LSL KrasG12D mice with p53-null mice (referred to as LSL KrasG12D p53 KO ). These mice allow cre-mediated expression of activated KrasG12D allele at a physiological level.…”

“…15,16 Previous work has focused upon AT2 cells, Clara cells (or variant Clara cells with low CC10 expression) and the putative bronchioalveolar stem cells (BASCs) as potential cells of origin for lung ADC. 12,14,17 However, to date, only AT2 cells have been conclusively identified as having the potential to be the cells of origin for lung ADC. 14,17 This raises the question of whether Clara cells, their restricted subpopulations or the newly identified candidate stem cells, termed distal airway stem cells, 18 alveolar epithelial progenitor cells (AECs) 19,20 and BASCs, 12 also have the capacity to give rise to ADC.…”

“…12,14,17 However, to date, only AT2 cells have been conclusively identified as having the potential to be the cells of origin for lung ADC. 14,17 This raises the question of whether Clara cells, their restricted subpopulations or the newly identified candidate stem cells, termed distal airway stem cells, 18 alveolar epithelial progenitor cells (AECs) 19,20 and BASCs, 12 also have the capacity to give rise to ADC. Current knowledge on the cellular origins of SCC, the second most common type of lung cancer, lags behind that of ADC, partly owing to the fact that squamous cells are not normally present in the respiratory epithelium, and therefore arise through either metaplasia (conversions between stem cell states) or trans-differentiation (conversions between differentiated cells).…”