Mapping longitudinal squamous cell lung cancer pathogenesis in pursuit of a preventative therapy

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Lung cancer kills more men and women than any other cancer. People with lung cancer have a 5% chance of living ten years. Around 75% of lung cancer is attributable to smoking but while rates of smoking are decreasing in the West they are spiralling in the Far East, India and Africa and the global burden will likely keep escalating higher than the current 2,000,000 cases per year. Despite the new treatments for advanced lung cancer with targeted genetic therapies, lung cancer survival did not change between 2004 and 2014. Lung cancers develop from the build-up of genetic damage in the individual cells of our lungs. This can cause some cells to begin growing faster than their neighbours and become what we call a dominant 'clone' of cells. The cells may change their appearance becoming detectable to doctors on the surface of the airways as what we call 'pre-cancerous lesions'. Importantly these cells must also adapt and hide from our immune system which should identify cells harbouring damaged genes and remove them; this is called 'immune evasion'. These lesions have the ability over time to progress to a full-blown cancer.We have discovered that pre-cancerous lesions in the airways are not always destined to become cancer. This observation brings with it several possibilities. Can we determine which precancerous areas are going to progress to cancer so we can deliver treatments earlier? By understanding why some lesions progress and some regress can we develop new therapies preventing lesion progression to cancer? Finally, does this knowledge enable us to potentially prevent airway cancers altogether? Over the last 15 years we have built internationally unique cohorts of patients with pre-cancerous airway lesions and followed the lesions and patients' clinical outcomes over time. We use biopsies to map the genetic and immune landscapes of the lesions. This has allowed us to compare lesions that progress to cancer to those that harmlessly regress. We have discovered a large number of genetic disturbances and can use these to accurately predict lesion progression. More recently we have also discovered a remarkable regenerative capacity of the lung: that in the right environment, highly damaged but microscopically 'normal' airway cells are replaced with cells undamaged by tobacco. However, we have no knowledge how these genetic and immune observations change over time. Only with this knowledge can we understand the key mechanisms involved in cancer development and then mimic these abnormalities in experimental systems. This would enable us to define which changes are the most important and which we could potentially target to stop lung cancer forming. This is the aim of this programme of work and we have five interlinking workstreams:1. Map how the genetic and cellular make-up of pre-cancerous lesions change over time2. Document the key interactions our immune system makes with pre-cancerous cells, potentially enabling us to develop therapies that would encourage our own immune system to eliminate these early lesions3. Using biopsies from patients already undergoing immune therapies for lung cancers we will use extra biopsies to examine the effects of an immune treatment on both pre-cancerous lesions and the normal epithelium - demonstrating this type of intervention is both possible and potentially effective4. We will examine what appears to be the key, but ill-understood role of overexpression (amplification) of a small part of chromosome 3 in pre-cancerous lesions. We have found all of the pre-cancerous lesions that progress in our cohort have the same repetition of a small part of chromosome 3; this region has several interesting genes on it which we believe are the key to a normal cell's ability to progress to a cancerous destiny5. We will use our knowledge to examine potential preventative therapies in a mouse model of early lung cancer