Cellular and molecular characterisation of epithelial tumour initiation

Background My research focus is driven by the fact that we still have little understanding of how hundreds of identified genetic aberrations impact tissue homeostasis leading to tumour development.

While hugely significant, work to date on large-scale sequencing efforts and a handful of well-characterised mutations has barely scratched the surface and the early stages of precancer tumour development remains poorly understood. Yet, it has a huge potential to improve success rates of early detection, prevention and treatment of cancer.

Recent sequencing studies of normal tissue suggest that acquiring putative oncogenic drivers is not sufficient to initiate tumour development.

This points towards elements, such as the cell of origin, differentiation state and the microenvironment, all playing a key role in mediating tumour initiation. My laboratory works on defining the early cellular and molecular events that drive tumour initiation and development.

In particular, we focus on how the cell of origin affects the differentiation trajectory of nascent tumour cells and dictates changes in the microenvironment thus enabling tumour growth and immune evasion.

Since the establishment of my laboratory five years ago, and with generous funding support from CRUK (CEA) we have made several important contributions to the understanding of how aggressive subtypes of breast and lung cancer develop1–4.

In particular, we have identified the transcription factor BCL11A as an oncogene in triple negative breast cancer (TNBC)1,4 and lung squamous carcinoma (LUSC)3.

Aims Going forward I would like to build on our successes to date by initiating a programme of research with two major aims: 1) characterising the role of BCL11A in epithelial tissue homeostasis and tumour development and; 2) comprehensive identification of cellular and molecular changes associated with the initiation of breast tumours.

Methods The proposed programme of research is comprised of two major work packages which will combine the use genetically engineered mouse models, RIME proteomics and single cell genomics to deliver on the two aims of the proposal. How results will be used? I am proposing an ambitious multidisciplinary programme of research for the next six years.

By the end of the PFA I expect to have a more comprehensive understanding of the cellular and molecular changes that take place in the lead up to epithelial tumour formation.

I anticipate this study will lead to the development of novel approaches for early detection, prevention and treatment of epithelial tumours.