Characterising cancer-associated fibroblast heterogeneity in lung cancer: relating molecular phenotype to function

Lung cancer causes more deaths every year than any other cancer. Although there have recently been developments in the types of treatment available, fewer than 15% of patients with this disease survive longer than five years. In order to develop new treatments, it is critical to have an understanding of how lung tumour cancers develop and spread. The environment surrounding a developing tumour (known as the tumour microenvironment) is key to its growth and spread (metastasis). One cell type that plays an important role in these processes is the fibroblast. Fibroblasts are found in both normal and cancerous tissues (where they are referred to as cancer-associated fibroblasts, or CAFs). In many cancers, the presence of these cells is related to shorter survival. CAFs have a number of effects, which promote the invasion of tumour cells into surrounding tissues and their subsequent spread. However, there is a large degree of variation within the fibroblast population, and some types of fibroblast are able to impair tumour growth and metastasis. How these different types of fibroblasts arise is currently unknown. Targeting the fibroblast types that encourage cancer development, in combination with chemotherapy, is a potential future strategy for treating tumours. This project, led by world-renowned researchers and using cutting-edge techniques, aims to identify the different types of fibroblasts present in one of the types of lung cancer; non-small cell lung cancer (NSCLC). We also aim to determine whether the different fibroblast types have different effects on the behaviour of tumour and immune cells. Our initial goal is to group CAFs according to the genes they express, using non-small cell lung cancer samples from patients. We shall achieve this using a new technique called droplet barcoded sequencing ('Drop-Seq'): the University of Southampton is currently one of the few centres in the world with this technology. Drop-Seq captures individual cells in separate droplets. Each droplet is labelled with its own unique barcode, allowing identification of the genes expressed by each individual cell. We will then identify specific markers for each CAF subtype, and examine whether these can be used to predict patient survival or guide treatment. I shall carry out experiments examining the effects of different CAF types on both tumour cell invasion and the ability of immune cells to infiltrate tumours. Through our work exploring these subtypes, we hope to to identify new targets for the diagnosis and treatment of non-small cell lung cancer. This research is being performed at the University of Southampton, a UK centre of academic excellence, involving new laboratory techniques (Drop-Seq) that have been implemented locally. During this project, I shall acquire knowledge of molecular pathology and bioinformatic skills, for the handling and analysis of large amounts of data. These attributes will be invaluable in my future academic career and in my clinical training as a cellular pathologist. In the long term, I hope that this research will identify new targets for the diagnosis and treatment of non-small lung cancer, This would enable the development of new therapies, improving the survival of patients with non-small cell lung cancer, with the potential to apply these findings to other types of cancer in the future.