Targeting purinergic signalling in pancreatic cancer

胰腺导管腺癌（PDAC）是一种致命的疾病，对新的和传统的抗癌治疗反应有限，主要是由于其特征的致密纤维化。有必要了解纤维化的癌症保护机制，以发现可能的治疗靶点。已知在高缺氧环境中具有细胞保护作用的途径之一是嘌呤能信号传导，但对其在胰腺癌中的重要性知之甚少。这一途径是高度可药物化的，并影响相关的生物过程，包括免疫细胞行为、细胞增殖和糖酵解。该项目的目的是询问嘌呤能信号在PDAC中的潜在作用。作为起点，我们使用公共数据库分析了PDAC患者中关键嘌呤能信号基因的表达。在初步的生物信息学分析中，基因表达已与临床数据相关联，以确定可能的靶点，受体P2Y2显示与临床结果相关，并与细胞粘附和免疫相关基因相关。该受体和其他潜在嘌呤能靶点的意义将通过PDAC的过表达、沉默和基于药物的方法进行研究，并使用3D多细胞球体模型确定潜在的新治疗靶点。

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that shows limited response to new and conventional anti-cancer treatments, largely as a result of its characteristic dense fibrosis. There is a need to understand the cancer-protective mechanisms of fibrosis to discover possible therapeutic targets. One pathway known to be cytoprotective in highly hypoxic environments is purinergic signalling, but little is known about its importance in pancreatic cancer. This pathway is highly druggable and affects relevant biological processes, including immune cell behaviour, cell proliferation and glycolysis. The aim of this project is to interrogate the potential role of purinergic signalling in PDAC. As a starting point, the expression of key purinergic signalling genes in PDAC patients has been analysed using public databases. In preliminary bioinformatic analysis, gene expression has been correlated to clinical data to identify possible targets, with the receptor P2Y2 showing a correlation with clinical outcome and a link with cell-adhesion and immune related genes. The significance of this receptor, and other potential purinergic targets will be studied using overexpression, silencing and drug-based approaches using a 3D multicellular spheroid model of PDAC, with the aim of determining potential novel therapeutic targets.