Lung cancer’s earliest warning signs are invisible to current tests, and doctors have no way to tell which pre-cancerous lesions will turn deadly and which will vanish on their own. This project tackles a blind spot in cancer medicine. Millions of people harbour abnormal cells in their airways that could become lung cancer, but clinicians lack biomarkers to predict progression. The researcher will analyse a unique biobank of tissue biopsies, sputum, and blood samples taken repeatedly from the same patients over time, tracking how pre-invasive lesions evolve at the genetic, epigenetic, and cellular level. If successful, the work could produce a clinical test that distinguishes dangerous lesions from harmless ones, sparing patients unnecessary treatment and focusing resources on those who need it. It could also identify the specific driver mutations and signalling pathways that push pre-cancerous cells toward invasion, opening the door to chemo-prevention strategies that block malignant clone expansion before cancer takes hold. The research is fundamentally about understanding the natural history of a hidden disease stage—but that understanding could directly reshape how lung cancer is caught and stopped.
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Our unique patient cohort enables the observation of the natural clinical history of pre-invasive lesions and the longitudinal biopsy sampling of individual lesions, newly arising lesions, control airway and samples such as sputum and blood/serum. It is likely that the epigenetic and genetic programming of pre-invasive cancer-propagating cells defines their proliferation, differentiation, survival and future treatment sensitivity, but this remains unexplored. I will use our unique tissue biobank to develop clinically useful biomarkers of pre-invasive lesion progression, document the biological steps in pre-invasive disease progression to invasion, determine the key mechanisms driving progression and design and challenge chemo-prevention strategies. Goal 1: Delineate the gene networks/pathways, epigenetic profiles and microenvironmental constraints associated with progression of pre-malignant lesions to invasive cancer 1.1 Discriminate biomarker accuracy in determining progressive from regressive lesions, enabling use as a clinical tool 1.2 Define the key driver oncogenes and pathways in progressive pre-invasive lesions to inform therapeutic strategies to block malignant clone expansion 1.3 Define the influence of the pre-invasive clone microenvironment on lesion progression Goal 2: Determine the cellular origin of pre-invasive lesions and the key mechanisms of clone expansion and progression to malignancy 2.1 Use a single-cell approach to define biological and f unctional subgroups of human basal cells and relate them to those of pre-invasive lesions 2.2 Examine the effects of mis-expression of key signalling pathways or driver mutations on basal cell clonal dynamics with a view to therapeutic intervention
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