Investigation of the role of the small GTPase RAC1 in invasion and metastasis of Small Cell Lung Cancer

Project Outline

Small cell lung cancer (SCLC) is an aggressive tumour, where 80% of patients have metastatic disease at diagnosis. Underlying this aggressiveness is intra-tumoural heterogeneity. Most SCLC tumours contain two different cell types, the majority being neuroendocrine (NE) with a small subset of non-neuroendocrine (non-NE). A phenotype switch from NE to non-NE generates the non-NE phenotype. Importantly, SCLC tumour heterogeneity is required for metastasis as co-operation between both cell types is needed. 

The mechanistic understanding of NE to non-NE transition and its role in SCLC invasion and metastasis has been hindered by the lack of plasticity of established SCLC cell lines. However, we are fortunate to have access to patient circulating tumour cell-derived explant models which can undergo NE to non-NE transition. Using these, we have recently shown that the small GTPase RAC1 is highly active in non-NE cells and promotes NE to non-NE transition. RAC1 is a molecular switch, cycling between inactive GDP and active GTP-bound forms. Active RAC1 has established roles in stimulating migration/invasion of several cancer cells, but its role in migration/invasion and metastasis of SCLC is unknown.  

Given the established roles of RAC1 in migration/invasion, its role in NE to non-NE transition and the requirement of both NE and non-NE cells for metastasis, this project aims to decipher the molecular and cellular mechanisms by which RAC1 signalling stimulates invasion and metastasis of SCLC both in vitro and in vivo. This project combines the expertise of the supervisory team in RAC1 signalling, matrix and SCLC biology with access to unique SCLC patient-derived models, presenting an unparalleled opportunity to uncover the mechanisms underpinning SCLC progression. 

The supervisory environment is supportive and values inclusivity and diversity. The student will present their work internally and at scientific conferences and receive mentoring for successful career progression alongside valuable training in transferable skills. 

Applications for this project are now open. Please complete your application on The University of Manchester website.