Squamous lung cancer (SQC) has been significantly more challenging to model than adenocarcinoma and progress in understanding its pathobiology and developing targeted therapeutics has been slow.
To address this unmet need we have developed a novel orthotopic model of SQC. We have refined/optimised a protocol for the expansion of primary murine tracheobronchial epithelial cells (mTBECs). We have optimised the genetic manipulation of primary mTBECs via multilocus CRISPR and lentiviral transduction so that clinically relevant genotypes can be rapidly recreated in primary mTBECs.
Further, we use inducible constructs so that genes of interest can be turned on and off at will throughout the natural history of the disease. The manipulated mTBECs are injected into the right lung of a syngeneic animal. Recipient mice therefore have an intact immune system and develop localised disease with the potential to metastasise.
We have demonstrated in pilot data that this approach generates early murine SQC lesions within 3 weeks and large invasive tumours at around 4 months in wild type immunocompetent animals.
This model can revolutionise the field - and lead to a dramatic reduction in the number of mice required to perform experiments; as well as refinements that reduce the ASPA severity limit to Moderate and remove the need for toxin administration.
Our scientific aims are to characterise the natural history of SQC in this novel syngeneic murine orthotopic model, to validate the model as being both reproducible and directly relevant to the human disease. Further, we will use luciferase-based imaging to ensure longitudinal studies on individual animals are feasible. Second we will apply the model to efficiently address key basic and translational issues: the necessity of a driving oncogene for SQC maintenance; the potential to use AKT inhibition for SQC chemoprevention; and a demonstration that it will have utility for studying the tumour immune microenvironment.