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

肺癌致死的男性和女性比其他任何癌症都要多。患有肺癌的人有5%的机会活十年。大约75%的肺癌是由吸烟引起的，但尽管西方的吸烟率正在下降，但在远东、印度和非洲，吸烟率正在螺旋式上升，全球的负担可能会继续上升，超过目前每年200万例的水平。尽管有靶向基因疗法治疗晚期肺癌的新疗法，但肺癌存活率在2004年至2014年期间没有变化。肺癌是由我们肺部单个细胞的基因损伤积累而来的。这会导致一些细胞开始比它们的邻居生长得更快，成为我们所说的显性的细胞‘克隆’。这些细胞可能会改变它们的外观，在呼吸道表面被医生检测到，这就是我们所说的“癌前病变”。重要的是，这些细胞还必须适应并躲避我们的免疫系统，免疫系统应该识别含有受损基因的细胞并将其移除；这称为“免疫逃避”。随着时间的推移，这些病变有可能发展为完全的癌症。我们已经发现，呼吸道中的癌前病变并不总是注定要变成癌症。这一观察带来了几种可能性。我们能否确定哪些癌前区域会进展为癌症，这样我们就可以更早地提供治疗？通过了解一些病变进展和一些退化的原因，我们能否开发防止病变进展为癌症的新疗法？最后，这些知识是否使我们有可能完全预防气道癌？在过去的15年里，我们建立了国际上独一无二的癌症前呼吸道病变患者队列，并随着时间的推移跟踪病变和患者的临床结果。我们使用活组织检查来绘制病变的遗传和免疫情况。这使我们能够将进展为癌症的损伤与无害退化的损伤进行比较。我们已经发现了大量的遗传干扰，并可以用这些来准确地预测病变的进展。最近，我们还发现了肺的一种非凡的再生能力：在合适的环境中，高度受损但在显微镜下看“正常”的呼吸道细胞被未被烟草破坏的细胞所取代。然而，我们不知道这些遗传和免疫观察是如何随着时间的推移而变化的。只有有了这些知识，我们才能理解癌症发展的关键机制，然后在实验系统中模拟这些异常。这将使我们能够确定哪些变化是最重要的，哪些可能是我们阻止肺癌形成的目标。这就是这项工作计划的目标，我们有五个相互关联的工作流程：1.绘制癌症前病变的基因和细胞构成如何随时间变化的图2。记录我们的免疫系统与癌前细胞之间的关键相互作用，这可能使我们能够开发出能够鼓励我们自己的免疫系统消除这些早期损害的疗法。使用已经接受肺癌免疫治疗的患者的活检组织，我们将使用额外的活检组织来检查免疫治疗对癌前病变和正常上皮的影响--证明这种类型的干预既是可能的，也是潜在有效的。我们将研究3号染色体的一小部分过度表达(放大)在癌前病变中的关键作用，但人们对此知之甚少。我们已经发现，在我们的队列中进展的所有癌前病变与3号染色体的一小部分具有相同的重复；该区域上有几个有趣的基因，我们认为这些基因是正常细胞向癌症方向发展的能力的关键。我们将利用我们的知识在早期肺癌的小鼠模型中检查潜在的预防性治疗。

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