Investigating the role of vascular endothelial-cell senescence driving resistance to DNA-damaging therapies and metastasis formation in lung cancer

肺癌是英国第三大常见癌症，5年生存率仅为19%，是全球主要死亡原因之一（世界癌症研究基金会，2020）。新辅助化疗（使用损伤DNA的药物）可以在手术前减少初始原发性肺癌的大小。然而，由于对这些类型药物的耐药性，癌症经常复发或扩散。耐药性发生的一种方式包括癌细胞的变化，它们会减慢并变得“衰老”。但重要的是，治疗诱导的衰老不仅可以发生在癌细胞中，也可以发生在我们身体中支持癌症的正常细胞中，也称为肿瘤微环境，甚至在其他非癌器官中。事实上，衰老与患者化疗的许多不良副作用有关，有报道称癌症幸存患者发展为与年龄相关的疾病，如血管病变。血管是肿瘤微环境的主要组成部分，因为它们是将血液和氧气输送到生长块的管道。最近，内皮细胞（排列血管的细胞）已被证明具有独立的作用，超越其典型的管道作用，作为从细胞中“吐出”的分子混合物的主调节器，可以控制相邻细胞的行为，甚至通过循环到达其他器官。粘着斑激酶（FAK）是在癌症中发现的分子，并且几种FAK阻断药物目前处于癌症治疗的临床试验中。然而，FAK在许多不同的细胞类型中表达，有时它们具有相反的功能，因此需要开发细胞类型特异性药物。在这种情况下，我们已经表明，在肿瘤小鼠模型中特异性靶向内皮细胞FAK导致肿瘤细胞对DNA损伤疗法的敏感性增加。重要的是，在人类临床环境中，我们已经表明肿瘤相关的内皮FAK表达与浸润性乳腺癌的分子亚型和预后相关，并且内皮细胞FAK活化独立地预测了新药物治疗的晚期乳腺癌的生存率提高。基于我们目前的工作，我们假设FAK是治疗诱导的内皮细胞衰老的调节剂，这可能是癌症扩散的机制。我们将确定调节这一点的分子，总体目标是设计新的方法来更好地治疗癌症扩散和耐药性。

Lung cancer is the third most common cancer in the UK, and with a 5 year survival rate of only 19% is one of the leading causes of death worldwide (World Cancer Research Fund, 2020). Neo-adjuvant chemotherapy (with drugs that damage the DNA) can reduce the size of initial primary lung cancers prior to surgery. However, the cancer often comes back or spreads because of resistance to these types drugs. One way that resistance can occur includes a change in the cancer cells where they slow-down and become 'senescent'. But importantly, therapy induced senescence can occur not only in cancer cells but also in normal cells of our bodies that support the cancer, also known as the tumour microenvironment, or even in other non-cancerous organs.In fact, senescence has been associated with many of the adverse secondary effects of chemotherapy in patients, with reports of cancer surviving patients developing age-related diseases such as vascular pathologies. Blood vessels are a major part of a tumour microenvironment, as they are the conduits by which blood and oxygen are delivered to the growing mass. More recently, endothelial cells (the cells that line blood vessels) have been shown to have an independent role, beyond their typical conduit role, as master regulators of a cocktail of molecules that are 'spat' out of the cell and can control how neighbouring cells behave or even travel through the circulation to other organs. Focal adhesion Kinase (FAK) is a molecule that is found in cancer and several FAK-blocking drugs are presently in clinical trials for cancer treatment. However, FAK is expressed in many different cell types with sometimes opposing functions in them, therefore cell-type specific drugs need to be developed. In this context, we have shown that specifically targeting endothelial-cell FAK in tumour mouse models leads to increased sensitisation of tumour cells to DNA-damage therapies. Importantly, in a human clinical setting, we have shown that tumour-associated endothelial-FAK expression correlated with molecular subtype and prognosis in invasive breast cancer and that endothelial-cell FAK activation independently predicts improved survival in neoadjuvant-treated advanced breast cancer. Based on our work so far we hypothesize that FAK is a regulator of therapy induced endothelial- cell senescence, which can be a mechanism by which cancer spreads. We will identify the molecules that regulate this with the overall goal of devising new ways to treat cancer spread and resistance to drugs better.