Development of a New Human Model of Lung Squamous Cell Carcinoma Progression

Why did we fund this project?

This award aims to develop human cell-based in vitro models to represent different stages of lung squamous cell carcinomas, replacing the use of mouse models in some studies.

Lung squamous cell carcinomas arise from epithelial cells accumulating genetic mutations until they become invasive cancerous cells. These cancers are very heterogeneous and are often associated with cigarette smoke. Prognosis is poor as the cancers are typically identified when the disease is advanced. A number of different approaches, including in vitro and in vivo methods, are used to study the disease and identify new treatment options but these methods currently do not mimic early preinvasive disease. Genetic mutations can be introduced into mice through breeding programmes, however these are often not the same mutations identified in patients. Carcinomas can also be induced via intratracheal administration of compounds or patient cells to create xenograft models. The severity of these models are defined as causing moderate suffering under the UK’s Animals (Scientific Procedures) Act 1986 due to the high tumour burden the animals experience and the impact on breathing. There are significant anatomical and molecular differences between mouse and human lungs, including the number of lobes, respiratory rate and systemic circulation.

Dr Carlos Lopez-Garcia will use genome editing techniques in patient basal cells to introduce cumulative mutations, commonly seen during carcinoma progression. These will represent various stages of disease from premalignancy to invasive cancer and reflect the heterogeneity of mutations seen in patients. Carlos will then determine how these cumulative mutations affect proliferation, gene expression, and genomic instability and validate the model by comparing this data to known stages of progression in patients.