Cell of Origin of Small Cell Lung Cancer: Inactivation of Trp53 and Rb1 in Distinct Cell Types of Adult Mouse Lung

SummarySmall cell lung cancer (SCLC) is one of the most lethal human malignancies. To investigate the cellular origin(s) of this cancer, we assessed the effect of Trp53 and Rb1 inactivation in distinct cell types in the adult lung using adenoviral vectors that target Cre recombinase to Clara, neuroendocrine (NE), and alveolar type 2 (SPC-expressing) cells. Using these cell type-restricted Adeno-Cre viruses, we show that loss of Trp53 and Rb1 can efficiently transform NE and SPC-expressing cells leading to SCLC, albeit SPC-expressing cells at a lesser efficiency. In contrast, Clara cells were largely resistant to transformation. The results indicate that although NE cells serve as the predominant cell of origin of SCLC a subset of SPC-expressing cells are also endowed with this ability.

► Cell-specific targeting in the lung is achieved using a series of Adeno-Cre viruses
► Loss of Trp53 and Rb1 in neuroendocrine cells effectively initiates SCLC in vivo
► Transformation of a rare SPC-positive cell by Trp53 and Rb1 loss initiates SCLC
► Loss of Trp53 and Rb1 in Clara cells does not lead to tumor formation