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%的肿瘤由“正常细胞”组成，如免疫细胞和伤口愈合细胞（称为成纤维细胞）。这些细胞被肿瘤“劫持”，帮助肿瘤生长，并保护它免受药物和抗肿瘤免疫细胞的侵害。这种被称为基质的肿瘤环境也会受到某些治疗方法的影响。尽管我们对癌细胞出了什么问题知道得很多，但对于基质细胞是如何改变的，以及它们是如何相互交流以帮助肿瘤生长和保护自己免受治疗的影响，我们知之甚少。最近，情况变得更加复杂，因为发现这些免疫细胞和成纤维细胞有不同的口味，其中一些有助于肿瘤，但有些实际上可能会对抗肿瘤。我们还发现了一种非常罕见的免疫细胞，叫做γ δ T细胞，它可能控制着这些不同类型细胞的进化。我们也知道一些治疗，特别是放射治疗，可以引起这些基质细胞的变化，并有可能促使它们进一步支持肿瘤生长和抵抗治疗。因此，研究来自这些细胞的信号，了解它们是如何促进肿瘤生长的，这一点很重要，这样我们就可以针对它们进行治疗。我们的目标是回答关于胰腺癌生物学的一些关键问题，以便我们能够确定新的治疗方法。具体来说，我们想要研究基质免疫细胞和成纤维细胞如何相互交流以促进肿瘤生长，γ δ T细胞如何改变这些基质细胞的味道，放射治疗如何使基质细胞更加支持肿瘤，以及我们如何预防它。我们将结合使用尖端技术：最先进的小鼠模型，发展出与人类肿瘤非常相似的胰腺肿瘤，小鼠放射治疗系统，使我们能够治疗肿瘤，同时尽量减少对周围健康组织的损害，类似于用于患者的放射治疗技术，一种称为空间转录组学的技术，使我们能够看到肿瘤切片中每个细胞的遗传“蓝图”，因此我们可以精确地将信号映射到单个细胞类型，以及一种称为单细胞RNA测序的技术，这使我们能够研究肿瘤中每个细胞的数千种变化。最令人兴奋的变化暗示着新的治疗策略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.