Spatial (dis-)organisation of lipid metabolism in chronic liver disease and cancer

在英国，大约四分之一的人口患有非酒精性脂肪性肝病（NAFLD）。NAFLD与肥胖和2型糖尿病有关，当过多的脂肪沉积在肝脏时就会出现。这可能导致更严重的情况，包括疤痕组织的形成（肝硬化）和肝癌的风险增加，肝癌的5年生存率不到15%。NAFLD是一个日益严重的问题，预计在未来10年将成为患者需要肝移植的头号原因。我们仍然不知道为什么肝脏中的脂肪会增加肝硬化和癌症的风险，尽管投入了大量资金，但到目前为止，药物治疗还不是很成功。肝脏中脂肪和瘢痕组织（纤维化）的沉积可能导致周围细胞代谢状态的改变。此外，肝脏由许多不同类型的细胞组成，它们可以通过“串扰”或信号传导相互作用。根据疾病的不同阶段，这些细胞可能具有不同的化学成分。我们将研究在纤维化形成过程中发生的一系列分子的变化。我们将使用一种称为质谱成像的特殊技术，根据不同组织区域和细胞类型的生物分子水平，对小鼠和人类的健康和疤痕肝脏切片进行分子快照。有了这项最先进的技术，我们可以在整个肝脏中建立一个“分子特征”，以发现正常细胞代谢是如何改变的，从而导致肝硬化的发展。这可以帮助我们预测可能预防、阻止或逆转这一过程的药物。肝硬化和NAFLD是发展为肝癌的危险因素。肿瘤中的癌细胞正在快速分裂，与“正常”细胞有不同的代谢需求。侵袭性较强或进展较晚的肿瘤，其化学成分可能与侵袭性较低或进展较晚的肿瘤不同。利用我们的质谱成像技术，我们将在肿瘤之间和肿瘤之间制造化学指纹，以了解新陈代谢是如何重新连接的。我们将根据特定突变和/或免疫细胞群的存在，将组织中的发现与血液联系起来，并将组织中的代谢特征与HCC的分子亚型联系起来。这项研究有可能揭示癌症患者体内存在的分子，用于临床早期检测的诊断测试，并根据分子特征决定最佳治疗方案。最后，我们将通过结合代谢物的空间分布信息和内源性细胞标记物的多重成像来研究免疫细胞与肝细胞的相互作用。这将需要方法开发，包括如何最好地执行数据集的数据融合。总的来说，我们的研究结果将揭示从脂肪肝和肝硬化发展为肝癌的疾病机制的前所未有的信息水平，这也可以改善诊断并为发现新的药物治疗提供信息。

Non-alcoholic fatty liver disease (NAFLD) is present in around one quarter of the population in the UK. NAFLD is associated with obesity and type 2 diabetes and arises when too much fat is deposited in the liver. This can lead to more serious conditions, including formation of scar tissue (cirrhosis) and increased risk of liver cancer, which has less than 15% survival rate over 5 years. NAFLD is an increasing problem and is expected to become the number one reason patients need a liver transplant in the next 10 years. We still don't know why fat in the liver increases the risk of cirrhosis and cancer, and treatment with drugs has not been very successful so far, despite big investment. The deposition of fat and scar tissue (fibrosis) in the liver may lead to a change in the surrounding cells' metabolic state. In addition, the liver is made of many different cell types, which can interact with each other by "cross-talk" or signalling. These cells may have different chemical compositions depending on the stage of disease. We will investigate the changes, in a range of molecules, which occur during the formation of fibrosis. We will use a special technique called mass spectrometry imaging to take molecular snapshots of healthy and scarred liver slices, in mice and humans, based on levels of biomolecules across different tissue regions and cell types. With this state-of-the-art technology, we can build a "molecular signature" across the liver to discover how normal cell metabolism is changed, leading up to the development of cirrhosis. This can help us to predict drugs that might prevent, stop or reverse the process.Cirrhosis and NAFLD are risk factors for developing liver cancer. Cancer cells in tumours are rapidly dividing and have different metabolic needs to "normal" cells. Tumours which are more aggressive or advanced may also have a different chemical make-up to those that are less aggressive/advanced. Using our mass spectrometry imaging technology, we will make a chemical fingerprint across and between tumours, to understand how the metabolism has been rewired. We will correlate findings in tissue to blood, and link metabolic signatures in tissue to molecular subtypes of HCC, based on the presence of specific mutations and/or immune cell populations. This research has the potential to uncover molecules present in patients with cancer that could be used to generate a diagnostic test in the clinic for early detection, and to decide on the best treatment based on the molecular signature. Finally, we will study the interaction of immune cells with liver cells, by combining information on the spatial distribution of metabolites with multiplex imaging of endogenous cell markers. This will require method development, including how best to carry out data fusion of the datasets. Overall our findings will reveal an unprecedented level of information on the disease mechanisms of liver cancer development from fatty liver disease and cirrhosis, which could also improve diagnostics and inform discovery of new drug treatments.