Multi-scale mechanochemical signals regulating cancer cell survival and invasive potential

实体瘤是复杂的多因素组织，由许多不同的细胞类型组成，这些细胞类型都有助于疾病的进展。肿瘤中的主要非细胞成分称为细胞外基质。这是一种在体内所有结缔组织中发现的蛋白质纤维网络，但在肿瘤中，它在支持癌细胞存活方面起着特别重要的作用。大多数组织中的细胞外基质通常非常柔软和柔韧，但研究人员发现，在许多癌症中，这种基质变得更加坚硬，这反过来有助于细胞生长并在称为转移的过程中远离原发肿瘤部位。我们已经发现了一些蛋白质，它们对肿瘤硬度的变化做出反应，以帮助保护癌细胞免受损伤，并帮助它们远离和转移。我们还发现，当用化疗治疗时，一些肿瘤变得更加僵硬，这可以使肿瘤生长得更多，并阻止化疗杀死肿瘤细胞。然而，我们仍然不知道细胞内哪些蛋白质有助于这一过程的全貌。在这个项目中，我们将使用一种称为蛋白质组学的技术来调查细胞中的所有蛋白质，并观察它们如何在水平和功能上变化以应对肿瘤基质硬度的增加。我们将使用复杂的显微镜技术来了解这些蛋白质如何帮助癌细胞逃避活样本中的化疗，并了解肿瘤周围的机械环境如何对应于免疫细胞如何攻击或协助肿瘤生长。最后，我们将使用所有数据分析头颈癌患者的样本，这些患者在治疗后有50%的复发率，迫切需要更好地了解疾病进展，以实现新的治疗方法。通过分析人体组织样本，并对患者进行特殊扫描以分析其肿瘤的硬度，我们将了解哪些蛋白质在具有较硬肿瘤的患者中发生了变化，以及其中一些蛋白质是否可以为临床医生提供信息以更有效地治疗这些患者。我们项目的结果将使人们更清楚地了解头颈癌组织中的“生物力学”与占据这些肿瘤的细胞之间的关系。我们将发现的新信息将有助于设计治疗患者的新方法，并为未来开发针对癌症生长和转移的新药找到新靶点。

Solid tumours are complicated multi-factorial tissues made up of lots of different ell types that all contribute to disease progression. The main non-cell component in tumours is called the extracellular matrix. This is a fibrous network of proteins found in all connective tissues in the body, but in tumours is plays a particularly important role in supporting cancer cell survival. The extracellular matrix in most tissues is usually quite soft and pliable but researchers have discovered that in many cancers, this matrix becomes stiffer and this in turn helps cells to grow and move away from the primary tumour site in a process called metastasis. We have discovered some proteins that respond to the changes in the tumour stiffness to help protect cancer cells from damage and help them move away and metastasise. We have also discovered that some tumours become even more stiff when treated with chemotherapy and this can make the tumour grow more and prevent the chemotherapy from killing the tumour cells. However, we still don't know the full picture of which proteins inside cells aide this process. In this project we will use a technique called proteomics to survey all proteins in cells and see how they change in levels and function in response to increasing tumour matrix stiffness. We will use complex microscopy techniques to learn how these proteins help cancer cells evade chemotherapy in live samples and understand how the mechanical environment surrounding tumours corresponds to how immune cells either attack or assist in tumour growth. Finally, we will use all of our data to analyse samples from patient with head and neck cancer, which has a 50% relapse rate after treatment and urgently requires better understanding of disease progression to enable new treatments. By analysing human tissue samples, and also taking special scans of patients to analyse the stiffness of their tumours, we will learn which proteins are changed in patients with stiffer tumours, and whether some of these proteins can provide information to clinicians to treat these patients more effectively. The outcome of our project will provide a much clearer understanding of the relationship between the 'biomechanics' in head and neck cancer tissues and the cells that occupy those tumours. The new information we will uncover will help to design new ways to treat patients and find new targets for future development of new drugs targeting cancer growth and metastasis.