The lung is comprised of a myriad of cell types, which range from epithelial to immune populations. Cells within the lung that acquire the first genetic perturbation, ultimately giving rise to cancer are coined cancer-initiating cells or “cells-of-origin”. Understanding where mutations first arise within the lung cellular compartment is important for developing clinically relevant models, such as genetically engineered mouse models (GEMMs). The “gold-standard” autochthonous lung cancer GEMMs are reliant on the delivery of Cre recombinase to the lung through adeno- or lenti-viral vector systems. However, the degree to which different viral vectors infect distinct cell types within the lung remains largely unknown, highlighting the need to better understand the cellular tropism of adeno- and lenti-Cre viruses.
To investigate the targeting biases of adeno- and lenti-viruses under the control of ubiquitous promoters, we utilised mT/mG fluorescent Cre-reporter mice. Through reporter switching, we identified distinct differences in infected cell types through histological and spatial analysis. Our analysis identified that the adeno-Cre virus displayed an even distribution of cellular trophism, compared to lenti-Cre viruses. Furthermore, all lentiviruses displayed an inherent bias towards infecting immune cell populations compared to epithelial cells. Taken together, we have highlighted distinct differences in cellular targeting which enable us to address the issue of lentiviral delivery in lung cancer modelling in vivo; particularly with newer lentiviral CRISPR-based models. These studies will inform the design of complex GEMMs through a combination of Cre-LoxP and CRISPR sgRNA systems.