Investigating Complex Crosstalk in the Pancreatic Cancer Microenvironment

胰腺癌的存活率很低，迫切需要更好的治疗方法。在胰腺癌中，高达90%的肿瘤可以由免疫细胞和伤口愈合细胞(称为成纤维细胞)等“正常细胞”组成。这些细胞被肿瘤“劫持”，以帮助肿瘤生长，并保护它免受药物和抗肿瘤免疫细胞的影响。这种被称为间质的肿瘤环境也会受到某些治疗的影响。尽管我们知道癌细胞出了什么问题，但我们对间质中的细胞是如何改变的，以及它们如何相互沟通以帮助肿瘤生长并保护自己免受治疗的影响，了解得远远不够。最近，情况变得更加复杂，人们发现这些免疫细胞和成纤维细胞有不同的味道，其中一些有助于肿瘤，但有些实际上可能起到对抗肿瘤的作用。我们还发现，一种非常罕见的免疫细胞，称为伽马三角洲T细胞，可能控制着这些不同口味的细胞如何进化。我们还知道，一些治疗，特别是放射治疗，可以引起这些间质细胞的变化，并潜在地促使它们进一步支持肿瘤的生长和对治疗的抵抗。因此，重要的是我们研究来自这些细胞的信号，并了解它们如何促进肿瘤生长，以便我们能够针对它们进行治疗。我们的目标是回答一些关于胰腺癌生物学的关键问题，以便我们能够找到新的治疗方法。具体地说，我们想要研究间质免疫细胞和成纤维细胞如何相互沟通以促进肿瘤生长，伽马三角洲T细胞如何改变这些间质细胞的味道，放射治疗如何使间质细胞更支持肿瘤，以及我们如何预防它。我们将使用尖端技术的组合：最先进的小鼠模型，它发展出与人类肿瘤非常相似的胰腺肿瘤，一种小鼠放射治疗系统，允许我们治疗肿瘤，同时将对周围健康组织的损害降至最低，类似于患者使用的放射治疗技术，一种被称为空间转录切除的技术，这让我们可以看到肿瘤切片中每个细胞的基因蓝图，这样我们就可以精确地将信号映射到单个细胞类型，以及一种名为单细胞RNA测序的技术，它允许我们调查肿瘤中每个单独细胞的数千个变化。暗示新的治疗策略的最令人兴奋的变化将在人类肿瘤中进行研究，并最终在模型中进行测试。

Pancreatic cancer has a very low survival rate and better treatments are urgently needed. In pancreatic cancer up to 90% of the tumour can be made up of 'normal cells' like immune cells and wound healing cells called fibroblasts. These cells get 'hijacked' by the tumour to help the tumour grow and to protect it from drugs and anti-tumour immune cells. This tumour environment, known as the stroma, can also be affected by certain treatments. Although we know quite a lot about what has gone wrong in the cancer cells, we understand far less about how the cells in the stroma become altered, and how they communicate with each other to help the tumour grow and protect itself from therapies. Recently the situation has become more complex, with the discovery that these immune cells and fibroblasts come in different flavours, some of which help the tumour, but some of which might actually act to fight the tumour. We have also identified that a very rare type of immune cell, called a gamma delta T cell, might control how these different flavours of cell evolve. We also know that some treatments, particularly radiotherapy, can cause changes in these stromal cells, and potentially drive them to further support tumour growth and resistance to therapy. Therefore it's important that we investigate the signals coming from these cells and understand how they can promote tumour growth, so that we can target them with therapies. We aim to answer some key questions about pancreatic cancer biology so that we can identify new treatments. Specifically, we want to investigate how the stromal immune cells and fibroblasts communicate with each other to promote tumour growth, how the gamma delta T cells can alter the flavour of these stromal cells, how radiotherapy can make the stromal cells even more tumour-supportive, and how we might prevent it.We will be using a combination of cutting edge techniques: state-of-the-art mouse models that develop pancreatic tumours very similar to human tumours, a mouse radiotherapy system that allows us to treat the tumours while minimising damage to surrounding healthy tissue similar to radiotherapy techniques used for patients, a technique called spatial transcriptomics, which allows us to see a genetic 'blueprint' of every cell in a slice of tumour so we can map signals precisely to individual cell types, and a technique called single-cell RNA sequencing, which allows us to investigate thousands of changes in each individual cell in a tumour. The most exciting changes that hint at new therapeutic strategies will be investigated in human tumours, and ultimately tested in models.