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

肺癌比任何其他癌症都要杀死更多的男性和女性。肺癌患者有5%的机会活10年。大约75%的肺癌可归因于吸烟，但尽管西方的吸烟率正在下降，但远东、印度和非洲的吸烟率却在螺旋式上升，全球负担可能会继续上升，高于目前每年200万例的水平。尽管晚期肺癌的靶向基因疗法有了新的治疗方法，但2004年至2014年期间肺癌生存率没有变化。肺癌是由肺部单个细胞中遗传损伤的积累而产生的。这会导致一些细胞开始比它们的邻居生长得更快，并成为我们所说的细胞的显性“克隆”。这些细胞可能会改变它们的外观，变得可以被医生在气道表面检测到，我们称之为“癌前病变”。重要的是，这些细胞还必须适应并隐藏我们的免疫系统，免疫系统应该识别携带受损基因的细胞并将其清除;这被称为“免疫逃避”。随着时间的推移，这些病变有能力发展成全面的癌症。我们发现，气道中的癌前病变并不总是注定会发展成癌症。这一观察带来了几种可能性。我们能否确定哪些癌前病变会发展为癌症，以便我们能够更早地进行治疗？通过了解为什么一些病变进展和一些退化，我们可以开发新的治疗方法，防止病变进展为癌症？最后，这些知识是否使我们能够潜在地完全预防气道癌？在过去的15年里，我们建立了国际上独特的癌前气道病变患者队列，并随时间推移跟踪病变和患者的临床结局。我们使用活检来绘制病变的遗传和免疫景观。这使我们能够比较进展为癌症的病变与无害的退化病变。我们已经发现了大量的遗传紊乱，并可以使用这些来准确地预测病变进展。最近，我们还发现了肺的一种非凡的再生能力：在适当的环境中，高度受损但微观上“正常”的气道细胞被未被烟草损伤的细胞所取代。然而，我们不知道这些遗传和免疫观察如何随时间变化。只有了解了这些知识，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，以及我们可能针对哪些变化来阻止肺癌的形成。这是本工作计划的目标，我们有五个相互关联的工作流程：1。绘制癌前病变的遗传和细胞组成如何随时间变化的图谱2。记录我们的免疫系统与癌前细胞的关键相互作用，可能使我们能够开发出鼓励我们自己的免疫系统消除这些早期病变的疗法。使用来自已经接受免疫治疗的肺癌患者的活检，我们将使用额外的活检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是可能的并且可能有效4。我们将研究在癌前病变中，3号染色体的一小部分过度表达（扩增）的关键作用。我们已经发现，在我们的队列中进展的所有癌前病变都具有3号染色体的一小部分的相同重复;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发展为癌症命运的关键。我们将利用我们的知识来研究早期肺癌小鼠模型的潜在预防性治疗方法

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